Newsletter A publication of the Controlled Release Society Volume 32 • Number 1 • 2015

What’s Inside

42nd CRS Annual Meeting & Exposition pH-Responsive Fluorescence Polymer Probe for Tumor pH Targeting

In Situ-Gelling Hydrogels for Ophthalmic Drug Delivery Using a Microinjection Device

Interview with Paolo Colombo

Patent Watch

Robert Langer Awarded the Queen Elizabeth Prize for Engineering

Newsletter

Charles Frey Vol. 32 • No. 1 • 2015 Editor Table of Contents

From the Editor ...... 2

From the President ...... 3

Interview Steven Giannos An Interview with Paolo Colombo from University of Parma ...... 4 Editor 42nd CRS Annual Meeting & Exposition ...... 6

What’s on Board Access the Future of Delivery Science and Technology with Key CRS Resources ...... 9

Scientifically Speaking pH-Responsive Fluorescence Polymer Probe for Tumor pH Targeting ...... 10 Arlene McDowell Editor In Situ-Gelling Hydrogels for Ophthalmic Drug Delivery Using a Microinjection Device ...... 12

Patent Watch ...... 14

Special Feature How to Be a Scientist and yet Write a Literary Novel ...... 16

Bozena Michniak-Kohn Chapter News Editor CRS New Zealand Local Chapter (NZCRS) Events in 2014 ...... 18

DDTR Updates Drug Delivery and Translational Research (DDTR) ...... 20

People in the News ...... 21

In the News ...... 23 Yvonne Perrie Calendar of Events Editor ...... Cover 4

Advertisers’ Index

Drug Delivery and Translational Research ...... Cover 2 18th Microencapsulation Industrial Convention ...... 11

Rod Walker Controlled Release Conference ...... 17 Editor

Cover image: Human Eye and Target ©Vladyslav Starozhylov / Shutterstock.com

1 From the Editor

Editors Charles Frey Steven Giannos Arlene McDowell Arlene McDowell University of Otago Bozena Michniak-Kohn New Zealand Yvonne Perrie Rod Walker Unexpected Things The CRS Newsletter is the official newsletter of the Controlled Release Society. The newsletter is published six ith the start of a new year, thinking can turn to wondering what the year will times annually, providing scientific and hold. iCal, doodle, and deadlines make sure we plan for some of the things we technical information pertinent to the do,W but there will always be unexpected things. controlled release community and news about society and chapter activities. Members can receive the newsletter via Unexpected things can be tragic, and I am reminded of the untimely passing of mail. The newsletter may also be viewed Marcus Brewster—a wonderful friend of so many in CRS. I am sure that Marcus online at controlledreleasesociety.org. would attest that unexpected things can also provide us with a great opportunity to Newsletter articles reflect only the views do something that we would not normally do. Personally, CRS has provided me with of the authors. Publication of articles or opportunities that I did not foresee (including co-editing a book, eating from a advertisements within the CRS Newsletter chocolate fountain in the penthouse at the New York Hilton, and going behind the does not constitute endorsement by the scenes at the Minneapolis zoo to fulfil a long-term wish to meet an opossum). This Controlled Release Society or its agents of products, services, or views expressed has all been through my contribution to CRS committees. Recently, I have been herein. No representation is made as to serving on the CRS Volunteer Recruitment Committee, where we have been looking the accuracy hereof, and the publication at strategies to broaden participation in the operation of CRS as well as enhancing is printed subject to errors and omissions. the volunteer experience. I strongly encourage you to get involved in a CRS Editorial contributions should be committee and see what unexpected things you can encounter. The CRS local directed to the CRS Newsletter Editors, chapters are an excellent way to begin your involvement and can enable you to ([email protected]) and are contribute more than your science to CRS. subject to the terms and conditions of the Editorial and Publication Release. Publisher assumes no responsibility for the In this issue of the CRS Newsletter you can read about a new initiative by the DDTR safety or return of artwork, photographs, journal to now consider publishing research that has a negative or unexpected finding. or manuscripts. This is an excellent initiative, and our lab group has often lamented the lack of this Requests for advertisement placement may type of forum. CRS members get free access to the online journal content. We also be directed to Susan Kohn; telephone have all our regular forums, including Scientifically Speaking, Patent Watch, and an +1.651.994.3812, or e-mail at skohn@ interesting interview with Prof. Paolo Colombo from Universita degli studi di Parma, scisoc.org. All advertisements are subject to “General Conditions of Sale.” Italy. Prof. Gregory Gregoriadis has also written a compelling account of his foray into writing a novel. Unauthorized reproduction in whole or in part is prohibited. Requests for permission Edinburgh is the place to be in 2015 for our CRS Annual Meeting. It seems like should be directed to the Editors at [email protected]. many of you agree, because a record number of abstracts have been submitted for this conference. I am excited to see the new format for the conference closing ©Copyright 2015 Controlled Release reception in Edinburgh. Plan to be there and to be open to the unexpected things Society. All rights reserved. that can happen. Controlled Release Society 3340 Pilot Knob Road St. Paul, MN 55121 U.S.A. On behalf of the CRS Newsletter editorial team, I wish you a happy, healthy, and Telephone: +1.651.454.7250 successful 2015. Facsimile: +1.651.454.0766 I will leave you with a relevant quote from Oscar Wilde: “To expect the unexpected Visit controlledreleasesociety.org or shows a thoroughly modern intellect.” e-mail [email protected] on questions about membership, meetings, publications, and services. Best wishes, n Contact [email protected] for information Arlene McDowell about exhibiting, advertising, or other visibility opportunities.

2 From the President

Art Tipton Southern Research Institute Birmingham, Alabama, U.S.A.

Celebrate Our History!

or many of us, January is the month when we come back You were probably already excited about the meeting in from a brief end-of-the-year break. Like many, I took some Edinburgh. Now you should be even more so given the timeF off as the year ended, reflected on 2014, and spent time opportunity to acknowledge Nicholas. Please also read more at planning for 2015. I unwound with a few books, including All the our website on how you can contribute and be part of this Light We Cannot See, the Anthony Doerr novel set during World opportunity, both to recognize Nicholas’s many accomplishments War II that is currently on best-seller lists, and the final book of in our field and contributions to our society and to invest in the Ken Follett’s Century Trilogy, Edge of Eternity. Those books got next generation of scientists. me thinking about history. As I write this in mid-January, we just commemorated Martin Luther King Jr. Day and reflected on his I want to provide a few more updates on the annual meeting. pivotal role in history. For us in North America, King is the While we appreciate and will build on our great history, as you person most identified with human rights, and he joins Nelson have probably seen from emails and other communications, we Mandela from Africa, Lech Walesa from Europe, Mahatma are working to add some changes so that we have the most Gandhi from Asia, and others around the world who as interactive and enjoyable meeting ever. Many of the leading individuals made a strong historical difference. scientists around the world have seen this updated format and are responding by submitting what looks to be a record-breaking In our own way, we at CRS have a great history we should also number of abstracts. Also, as you know, we will have an increased commemorate. For many years we have acknowledged our leaders industry focus, once again renewing our commitment to that with awards. In 2009 we created a special way to acknowledge the fruitful exchange between academia and industry that has been luminaries in our field with a Foundation Award. In that year and an integral part the rich CRS history. Our annual banquet, once subsequent years we have honored Joe Robinson, Jorge Heller, a highlight of our yearly gathering, has over recent years been Tsuneji Nagai, Sun Wan Kim, and Sandy Florence. I am pleased more sparsely attended due to extra costs for attendees. This year to announce we will continue this recognition in Edinburgh in we have developed an updated event, included in the meeting 2015, recognizing Nicholas Peppas. In previous years CRS has registration, that will be a fun taste and experience of Scottish recognized these leaders by establishing a one-year postdoctoral history. This event will be a great networking experience for all position for one individual in a lab of their choosing. Going attendees. forward we are electing to use those funds to more aggressively sponsor young scientists to attend our annual meeting. With this Finalize your plans to join us in Edinburgh this July. Come and new focus, the program is designed to support multiple students celebrate the history of CRS, and build (or start) your own to attend the CRS meeting so those students have a chance to history within our society. Plan a few extra days to enjoy experience the signature event in our society and to learn from Edinburgh and Scotland, and as I am telling people, “Come and meet with other delivery scientists. This new focus is for the Science, Stay for Some Haggis!” n consistent with the long-term vision of CRS and provides an even better way to honor our luminaries and continue the wonderful history of our society.

3 Interview

An Interview with Paolo Colombo from University of Parma

Vishwas Rai1 and Bozena B. Michniak-Kohn2

Dr. Paolo Colombo is the first Italian researcher in pharmaceutical technology. Then an international expert I progressed to an assistant and then an associate professor in in the field of his group together with Ubaldo Conte and Carla Caramella. pharmaceutical In 1986 I won a position as a full professor in Parma, where technology, swellable the Faculty of Pharmacy called on me to implement the matrices for oral research and teaching in pharmaceutical technology. The delivery of drugs, faculty, in particular the dean, Tullo Vitali, supported me a lot, Colombo (left) with Nicholas Peppas (right) iontophoresis, nasal and and when the faculty got a new building I decided to move on a spring day in Parma for Verdi composer pulmonary my family and stay in Parma. There are also collateral reasons celebrations. administration of drugs, to the scientific interests that convinced me to stay there, such and pharmaceutical as the music (Parma is the city of Verdi and Toscanini), the micro- and nanoparticles and generic preparations. excellent food, and the good quality of life in this city.

Dr. Colombo received his Pharm.D. (master course in pharmacy) Q You have worked closely in collaboration with different professors in November 1968 and an honorary Ph.D. from the University and scientists. What are your closest ties? What do you think made of Athens in 2010. He joined the Università degli studi di Parma these relationships so special? as a professor of pharmaceutical technology in 1986 and since A Apart from the colleagues mentioned before, I have to then has published over 250 articles in international journals, acknowledge Piero Catellani, who collaborated with me in made over 275 communications to scientific meetings, and Parma on many research subjects, and my first students there, presented over 130 lectures as an invited speaker on various now professors in Parma: Patrizia Santi and Ruggero Bettini. research topics. He has been a part of peer societies such as CRS, The risk to miss someone is high, but I cannot forget the time Italian Pharmaceutical Technology Teachers, Italian Society of spent and collaborations done with Michel Traisnel, Jean Pharmacokinetics and Biopharmaceutics, Industrial Pharmacists Claude and Anne Guyot in Lille, Pierre Buri and Eric Association, American Association of Pharmaceutical Scientists Doelker in Geneva, Dominique Duchene, Francis Puisieux, (AAPS), European Federation for Pharmaceutical Scientists, and Patrick Couvreur and Elias Fattal in Paris Sud, Bob Langer at Association de Pharmacie Galénique Industrielle. Massachusetts Institute of Technology, Richard Guy at University of California, San Francisco, Tsuneji Nagai in During his career, Dr. Colombo has received many awards, Tokyo, Hans Junginger in Leiden, Dimitri Rekkas in Athens, including the Award for Scientific Production at the University and Maria José Alonso in Santiago de Compostela. However, of Pavia (1973), Colorcon Award (1991), Jorge Heller Journal of what gave decisive input to my career was the scientific and Controlled Release Outstanding Paper Award (1999), Maurice- friendly collaboration with Nicholas Peppas at Purdue. We Marie Janot Award for Pharmaceutical Sciences (2004), CRS spent many days together working on matrices, swelling, Reiner Hofmann Award (2007), CRS Founders Award (2014), disintegration, and release mechanisms. Very often this was and Ralph Shangraw IPEC Award (2014). He is a foreign done in the car, moving around Italy for meetings or lectures. correspondent of the Association Française des Enseignants de It continues to be a fantastic interaction between a pharmacist Pharmacie Galénique, a foreign member of the Academie de and a chemical engineer. We have a common passion that Pharmacie Française (1999), and an AAPS fellow (1996). helps: opera. We exchanged many students for collaborative His recent projects are related to microparticle design and testing research projects as well as Ph.D. theses. for lung delivery, thalidomide for telangiectasia by nasal delivery (Telethon), gastroretentive dosage forms for drug combination Q What are some of your most interesting research projects? modified release, inhalation therapy in tuberculosis, and new dry powder inhalation in cystic fibrosis. A The most interesting has been the Geomatrix technology for oral drug delivery control. The idea of modifying the release Q How did you get to join the University of Parma, and what kinetics without changing the matrix composition was first inspired you to stay at this place for all of your working career? described in a thesis done in Pavia by one of my students, Didi Sangalli. She became a young professor in Milan, but A I graduated in pharmacy in Pavia, an old university close to she left us prematurely five years ago. Didi’s thesis provided Milan, studying for my thesis with Aldo La Manna, who was the scientific basis for making the matrix prototypes appear as partially coated swellable matrices. The coating position 1 Chrono Therapeutics Inc., Hayward, CA, U.S.A. 2 Ernest Mario School of Pharmacy, Rutgers–The State University of on the matrix core affects the matrix swelling and, as a New Jersey, U.S.A. consequence, the drug release rate and kinetics. However, 4 ideas can become products if a mind open to the market Q What is role of government in academic research in Italy? What is contributes, and in this case the fortune was to meet Jacques the status of government-sponsored and private research funding? Gonella, the founder of Yagotech, who put the product on How has that changed over the years? the U.S. market. Today, the evolution of this product is A Academic research today is not supported enough by national another matrix delivery system known as Dome Matrix, governmental funding. The economic situation in recent years which is a modular system used for drug combination reduced the possibilities of access to funding. This access is products. still too much related to lobbying. In contrast, being renowned in research opens one to contracts with companies. Q Please list the five publications from your research lab that were Today, 90% of my funds come from industry. I hope that will most significant in your research career. continue. A Harland, RS, Gazzaniga, A, Sangalli, ME, Colombo, P, Peppas, NA. Drug/polymer matrix swelling and dissolution, Q How has the European economy affected research activity in Italy Pharm. Res. 5(8): 488-494 (1988). in last few decades? Colombo, P, Conte, U, Gazzaniga, A, Maggi, L, Sangalli, A There is a great expectation from the new EU program ME, Peppas, NA, and La Manna, A. Drug release Horizon 2020, and we have applied to this program recently. modulation by physical restrictions of matrix swelling, Int. J. The European Union is now favoring the contacts with Pharm. 63: 43-48 (1990). European industries from other countries. De Ascentiis, A, Bettini, R, Caponetti, G, Catellani, PL, Q For international students and professionals, would you suggest Peracchia, MT, Santi, P, Colombo, P. Delivery of nasal advanced education in Italian schools? What is the language for powders of beta-cyclodextrin by insufflation, Pharm. Res. day-to-day activities? Is financial aid available to foreign 13(5): 734-738 (1996). students? Young, PM, Cocconi, D, Colombo, P, Bettini, R, Price, R, A Education in Italy is certainly advantageous for classic Steele, DF, Toby, MJ. Characterization of a surface modified disciplines. Also, technological fields that are very advanced dry powder inhalation carrier prepared by “particle in the country attract researchers in science. We receive many smoothing,” J. Pharm. Pharmacol. 54: 1339-1344 (2002). students from EU countries because of the Erasmus program, Sonvico, F, Mornet, S, Vasseur, S, Dubernet, C, Jaillard, D, which allows EU students to follow undergraduate courses at Degrouard, J, Hoebeke, J, Duguet, E, Colombo, P, and foreign universities and have recognition of the credits at Couvreur, P. Folate-conjugated iron oxide nanoparticles for their original universities. Presence in class requires a solid tumor targeting as potential specific magnetic minimum understanding of the Italian language. In a hyperthermia mediators: Synthesis, physicochemical laboratory, the language for communication and collaboration characterization and in vitro experiments, Bioconjugate is English. It is not easy to find a local grant for a foreign Chem. 16: 1181-1188 (2005). student. Sometimes the Italian embassy in the country of origin provides financial support. Q Please list the five most important publications (not from your lab) that you think have had the greatest impact in the Q Your main hobbies are skiing and sailing. What fascinates you pharmaceutical science field during your research career. about these sports? What else do you do like to do in your spare time? A Peppas, NA. Analysis of Fickian and non-Fickian drug release in polymers, Pharm. Acta Helv. 60: 110-111 (1985). A The two sports have in

common being Brigger, I, Dubernet, C, Couvreur, P. Nanoparticles in cancer outdoors. Maybe I like therapy and diagnosis, Adv. Drug Delivery Rev. 54(5): 631- them since I am always 651 (2002). inside during working Gref, R, Minamitake, Y, Peracchia, MT, Trubetskoy, V, hours in a lab or Torchilin, V, Langer, R. Biodegradable long-circulating classes. In reality, these polymeric nanospheres, Science 263(5153): 1600-1603 sports are also shared (1994). by my family, and they are a good opportunity Potts, RO, Guy, RH. Predicting skin permeability, Pharm. The Colombo family on a magnificent for keeping all of us in Res. 9(5): 663-669 (1992). winter day in the Livigno Alps (Italy): contact. Paolo, Gaia (associate professor at Amidon, GL, Lennernäs, H, Shah, VP, Crison, JR. A I like to spend my University of Ferrara), Miti (letter theoretical basis for a biopharmaceutic drug classification: free time with my professor), and Marcello (a police officer The correlation of in vitro drug product dissolution and in students too. Every in Rome). vivo bioavailability, Pharm. Res. 12(3): 413-420 (1995). year, we organize a few days all together for skiing or mountaineering. n

5 42ND CRS ANNUAL MEETING & EXPOSITION

July 26–29, 2015 Edinburgh, Scotland

CREATING VALUE THROUGH CUSTOMISED DELIVERY

The Annual Meeting Call for Abstracts closed in mid-January 2015. Nearly 1,000 abstracts were submitted from individuals representing 56 countries. “CRS leadership is excited about the strategic changes planned for this meeting,” said Susan Kohn, CRS Executive Director. “The six-year high in abstract submissions is both an enthusiastic endorsement of the new scientific session format and an early indicator of strong attendance in Edinburgh. The CRS Board and Program Planning Committees are delighted with the response.” The Annual Meeting website is your go-to link to the latest scientific content, discounted housing, online registration, exhibit and sponsorship opportunities, and schedule-at-a-glance. Be sure to bookmark controlledreleasesociety.org/meeting and visit often.

NEW! 90-minute scientific session format moderated by a CRS Fellow or society leader Scientific Sessions: New Format to Deliver 40 minutes Two Invited Speakers: 1 from industry, 1 from academia a Balanced Program Watch the website and the next issue of Research Highlight Talks: 5 chosen from submitted abstracts the CRS Newsletter for scientific sessions 30 minutes developed using the new 90-minute format. Speakers will prepare a corresponding poster presentation This approach will offer meeting attendees expanded opportunities to exchange 20 minutes Q&A Session with All Speakers information on cutting-edge research, new technologies, and emerging growth areas.

Mini-Symposia: Multiple Perspectives from Invited Speakers Mini-symposia offer in-depth knowledge into a specific area of delivery science and technology, featuring multiple invited speakers sharing their research on the topic. Symposia descriptions, moderators, and invited speakers are listed on the Annual Meeting website. Cost-Effective Encapsulation for Industrial Applications: Next-Generation Vaccine Development and Delivery Limitations and Solutions Technologies Moderators: Doug Dale, Dupont Industrial Biosciences, U.S.A.; Moderators: Sevda Senel, Hacettepe University, Turkey; and and Igor Bodnár, Firmenich, Switzerland David Brayden, University College Dublin, Ireland

European Technology Platform on Nanomedicine: Therapeutic Cancer Nanomedicines Translation of Nanomedicines Moderators: Lawrence Mayer, Celator Pharmaceuticals, Inc., Moderator: Patrick Boisseau, Nanomedicine European U.S.A. and Canada; and You Han Bae, University of Utah, Technology Platform, Germany U.S.A.

Modeling and Simulation of Oral Absorption – A Progress Report from the EU/IMI Project OrBiTo Moderators: Peter Langguth, Johannes Gutenberg University of Mainz, Germany; and Clive Wilson, University of Strathclyde, United Kingdom Opening Comments: A Tribute to Dr. Marcus Brewster

6 Premeeting Workshops: Deep Discussion on Diverse Topics Workshops offer focused presentations on specific topics by noted speakers and are open to a limited number of participants for an additional fee. All workshops will be held prior to the annual meeting. Advance registration and payment required. You may register for a workshop even if you do not plan to attend the annual meeting.

Advanced Pulmonary Drug Delivery: From Generating Introduction to Microencapsulation Aerosols to Overcoming Biological Barriers Saturday–Sunday, July 25–26 Saturday, July 25 (one-day workshop) (1.5-day workshop) Organizers: Claus-Michael Lehr, Saarland University, Organizers: James Oxley, Southwest Research Germany; and Heidi Mansour, University of Arizona, Institute, U.S.A.; and Jean-Antoine Meiners, U.S.A. Laboratoire Meiners Sàrl, Switzerland

Delivery of Therapeutic Bioconjugates: From Polymer Ocular Drug Delivery – Challenges of Matching New Conjugates to Antibody-Drug Conjugates Technologies with Drug Pharmacokinetics Sunday, July 26 (half-day workshop) Saturday, July 25 (one-day workshop) Organizer: Roger Pak, Pfizer Inc., U.S.A. Organizers: Ilva Rupenthal, University of Auckland, New Zealand; and Michael O’Rourke, Graybug, LLC, U.S.A.

Plenary Speakers: Internationally Recognized Experts This year, CRS is pleased to offer a featured speaker on each day of the meeting. The first plenary speaker is slated to address the general audience on Sunday, July 26, at 3:00 p.m.

Polymers and Nanomedicines – The Promises and Customized Drug Delivery: Pitfalls of New Materials A Personal Odyssey

Cameron Alexander Vincent H. L. Lee Head of the Division of Drug Delivery School of Pharmacy, Faculty of Medicine, and Tissue Engineering, School of Pharmacy, Chinese University of Hong Kong University of Nottingham, United Kingdom

Global Efforts and Successes in Needle-Free Ligand-Directed Therapy and Molecular Imaging Peptide Delivery Based on In Vivo Phage Display Technology

María José Alonso Renata Pasqualini University of Santiago de Compostela, University of New Mexico Cancer Center, Spain, and coordinator of the TRANS-INT U.S.A. European Consortium

42nd CRS Annual Meeting & Exposition continued on page 8 7 42nd CRS Annual Meeting & Exposition continued from page 7 Registration Opens Late March 2015 Annual Meeting Program Committee 2015 CRS Registration Types and Fees

Chair: All CRS registration fees are in U.S. dollars (USD) Justin Hanes, Johns Hopkins University, U.S.A. EARLY REGISTRATION Deputy Chair: (March 23–May 14, 2015) Kinam Park, Purdue University, U.S.A. Member Meeting PLUS Nonmember Team Members: Rate Membership Rate Adah Almutari, University of California, U.S.A. Regular $875 $1,045 $1,050 You Han Bae, University of Utah, U.S.A. Student* $450 $500 $495 Igor Bodnar, Firmenich, Switzerland Postdoc* $495 $550 $525 David Brayden, University College Dublin, Ireland REGULAR REGISTRATION Doug Dale, DuPont Industrial Biosciences, U.S.A. (after May 14, 2015) Bill Lambert, MedImmune, U.S.A. Yvonne Perrie, Aston University, United Kingdom Member Meeting PLUS Nonmember Suzie Pun, University of Washington, U.S.A. Rate Membership Rate Ilva Rupenthal, University of Auckland, New Zealand Regular $1,075 $1,245 $1,249 Ron Smith, Merck & Company, Inc., U.S.A. Student* $540 $590 $585 Postdoc* $585 $640 $615

*Full-time student/postdoc rates: full-time students and postdocs qualify for discounted registration rates. Proof of graduate student or Book Your Room: Many Choices at a Variety of postdoctoral research status will be required when registering for the Price Points annual meeting.

This year, CRS-negotiated accommodations include a large variety of hotels offering discounted rates. The best news? You can view, select, and book your choice of accommodations from one link to Marketing Edinburgh Ltd./Convention Edinburgh—the only housing bureau authorized to book CRS Annual Meeting hotel reservations. Don’t wait until the June 11 reservation deadline—book now to get the accommodations that best fit your needs. Annual Meeting Closing Reception Edinburgh: Since 1787, the Assembly Rooms in Edinburgh have been in continuous use Feel Like Royalty in a New Event for grand assemblies, balls, musical Modern, Dynamic Capital Included in Your performances, and many other public Registration and private events. CRS is proud to be Trip Advisor describes Edinburgh as “a cultural tapestry Fee hosting a Closing Reception with drinks that’s visually defined by hills, cathedrals, and the bold and hors d’oeuvres at this UNESCO stone turrets of Edinburgh Castle.” While Edinburgh is rich World Heritage Site on Tuesday, July 28, in connections to the past, it’s known by many names in this modern era, including the “world’s leading festival from 7:30–10:00 p.m. You’ll enjoy the sights, city.” Come early or stay after the annual meeting to sounds, and flavors of Scotland as all come together to celebrate. celebrate with thousands of visitors who take in the More details to come! Edinburgh Jazz and Blues Festival (July 17–26), Royal Military Tattoo (August 7–29), and Edinburgh International Festival (August 7–31).

While visiting this modern, dynamic capital, you will witness an economy dominated by financial services, scientific research, higher education, and tourism. The city has long been known as a center of education, Courtesy Sheraton Edinburgh particularly in the fields of medicine, the sciences, and engineering. How’s that for fitting in? Book your room today!

8 What’s on Board? What’s on Board?

Access the Future of Delivery Science and Technology with Key CRS Resources

Essential Delivery Science Webcasts Comprehensive Guides to Delivery Science

CRS is committed to delivering content that’s relevant, peer Build your knowledge reviewed, and convenient to access from around the globe. base with the CRS Recorded presentations from the annual meeting are available to Advances in Delivery CRS members indefinitely and to registered meeting attendees Science and Technology for one year after the meeting date. Take advantage of this book series. CRS books important benefit of membership, on demand. deliver essential knowledge on delivery View over 70 recorded presentations from the 2014 Annual science and technology, Meeting. Topics include: written and edited by scientific • Advances in Drug Delivery to the Eye and Lung authorities and opinion • Advances in Process Engineering leaders from • Advances in RNA and DNA Delivery around the globe. • Cells as Delivery Vehicles • Controlled Release Applications in Food, Feed, and Beverages The series includes: • Controlled Release of Actives in Consumer Products • NEW! Amorphous Solid Dispersions • Innovations in Micro- and Nano-Based Delivery Shah, N.; Sandhu, H.; Choi, D.S.; Chokshi, H.; Malick, A.W. • Innovations in Oral Drug Delivery (Eds.) • Intracellular Delivery of Nucleic Acids and Proteins • Nanoparticle-Based Delivery to the Brain • Controlled Release in Oral Drug Delivery • Nanoparticles in Tumor Treatment Wilson, Clive G.; Crowley, Patrick J. (Eds.) • Overcoming Barriers in the GI Tract • Controlled Pulmonary Drug Delivery • Proteins, Peptides, and Vaccines Smyth, Hugh D.C.; Hickey, Anthony J. (Eds.) • Transdermal Delivery • NEW! Focal Controlled Drug Delivery Domb, A.J.; Khan, W. (Eds.) Recorded presentations are also available for the 2009–2013 annual meetings. n • Fundamentals and Applications of Controlled Release Drug Delivery Members Highlight the Value of Webcasts Siepmann, Juergen; Siegel, Ronald A.; Rathbone, Michael J. (Eds.) Nilesh Shah’s presentation • Long Acting Animal Health Drug Products “shows clear examples of true market applications of McDowell, Arlene; Rathbone, Michael J. (Eds.) encapsulation and controlled • Long Acting Injections and Implants release technologies outside Wright, Jeremy C.; Burgess, Diane J. (Eds.) of the pharma market: marine coatings, wood, • NEW! Nano-Oncologicals: New Targeting and Delivery textile and personal care.” Approaches — Nicole Papen-Botterhuis, TNO, the Netherlands Alonso, María José; Garcia-Fuentes, Marcos (Eds.) • RNA Interference from Biology to Therapeutics Howard, Kenneth A. (Ed.) Steven Sutton’s meta-analysis provides “invaluable info for • NEW! Subunit Vaccine Delivery designing oral studies in different Foged, C.; Rades, T.; Perrie, Y.; Hook, S. (Eds.) species.” n • NEW! Targeted Drug Delivery: Concepts and Design — Peter Cheifetz, Merial Inc. Devarajan, Padma V.; Jain, Sanyog (Eds.)

For more information, visit controlledreleasesociety.org. n 9 Scientifically Speaking

pH-Responsive Fluorescence Polymer Probe for Tumor pH Targeting

Yuki Hiruta,a,b Takaaki Funatsu,a Yutaro Maekawa,a Minami Matsuura,a Teruo Okano,c and Hideko Kanazawaa

Introduction acids (NEAA) with 10% fetal bovine serum (FBS) with 5% CO2. The consistent differences between tumor cells and normal cells Cultured cells were exposed to ID48S10-FL (400 μg/mL) in

are often not enough to distinguish tumor cells from normal MEM at pH 7.4 or 6.8 at 37°C for 4 h with 5% CO2. After cells in order to destroy only cancer cells selectively. Features of incubation, HeLa cells were rinsed with Dulbecco’s phosphate- the tumor microenvironment that are slightly different from buffered saline (DPBS) three times. HeLa cells were fixed with normal tissues include acidity, hypoxia, overexpressed proteases, 4% paraformaldehyde phosphate buffer solution (Wako) for 20 and so on.1 Therefore, we have developed a highly sensitive pH- min and rinsed with DPBS twice. Samples were visualized with responsive fluorescence polymer probe for selective imaging of glass-bottom dishes by a confocal laser scanning microscope. acidic tumor cells, because the probe will only respond to the weakly acidic tumor environment (Figure 1). Results and Discussion Sharp transmittance curves of ID48S10 in aqueous buffer Poly(N-isopropylacrylamide) (PNIPAAm) exhibits thermally solutions were observed regardless of pH (Figure 3). LCST and reversible soluble–insoluble changes in an aqueous solution in zeta potentials of ID48S10 as a function of pH values are shown response to temperature changes across a lower critical solution in Figure 3B. The zeta potentials of ID48S10 showed only temperature (LCST) at 32°C. Additionally, the LCST of negative values. As the pH value decreased, the zeta potential PNIPAAm can be increased to near body temperature with more increased. The charge neutralization of SMZ by protonation of

hydrophilic comonomers, such as N,N-dimethylacrylamide the sulfonamidic group (-SO2NH-) with decreasing pH values (DMAAm). pH-sensitive monomers are copolymerized with can be attributed to increasing zeta potential as well as to PNIPAAm, and a phase transition can also be induced by a hydrophobization of polymer chains. Consequently, LCST of change in the specific pH near pKa of pH-sensitive monomers, such as sulfamethazine acrylamide (SMZ). Therefore, we designed a pH- and temperature-responsive fluorescence polymer probe (ID48S10-FL), comprising p(NIPAAm42%-co- DMAAm48%-co-SMZ10%), which exhibited phase transition via environmental pH change at 37°C, near body temperature (Figure 2). pH-Dependent intracellular uptake of ID48S10-FL was evaluated.

Experimental Methods ID48S10 was synthesized by reversible addition-fragmentation chain transfer (RAFT) radical polymerization. RAFT polymerization can control the molecular weight of polymer Figure 1. Tumors absorb a fluorescence probe under weakly acidic conditions. chains with narrow molecular-weight distribution. The pH- dependent LCST of the polymer was determined by measuring the optical transmittance in aqueous buffer solutions (0.5 w/v%) at 500 nm. ID48S10 was grafted to 5-aminofluorescein (FL) using the formation of an amide bond between the carboxyl end group of ID48S10 and the amino groups of FL, to obtain ID48S10-FL.

HeLa cells were seeded into 35 mm glass-bottom dishes (5 × 104 cells, 2 mL/dish) and cultured for one day at 37°C in minimal essential medium (MEM) with nonessential amino

a Keio University, Faculty of Pharmacy, Minato-ku, Tokyo, 105-8512, Japan. b Corresponding author. E-mail: [email protected]. c Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Tokyo 162-8666, Japan. Figure 2. The design of the pH-responsive fluorescence polymer probe. 10 Conclusion In conclusion, we have developed a highly sensitive pH- and temperature-responsive fluorescence polymer probe. ID48S10 showed drastic phase transition (hydrophobic/hydrophilic) change at pH-dependent temperatures. While the zeta potential closed to 0 mV by neutralization of the SMZ moiety, LCST temperatures decreased with decreasing pH values. ID48S10-FL was internalized by HeLa cells at only the pH of 6.8, confirm- ing the pH-dependent cellular uptake of ID48S10. These results indicated that a pH- and temperature-responsive fluorescence Figure 3. (A) Temperature-dependent optical transmittance of ID48S10 as a function of pH; (B) LCST and zeta potential of ID48S10 as a function of polymer probe has the potential to be applied for selective imag- pH. Reprinted from Hiruta et al. (2015), with permission from Elsevier.2 ing of acidic tumor cells. Thus, these methods could provide new opportunities for the development of molecular diagnostics, drug deliveries, biosensing, and bioimaging technologies. ID48S10 drastically decreased as the pH value decreased. ID48S10-FL was incubated at two pHs (6.8 and 7.4). While the References green fluorescence derived from ID48S10-FL was hardly 1. Tian, L, Bae, YH. Cancer nanomedicines targeting tumor observed at pH 7.4, fluorescence can be clearly observed at pH extracellular pH, Colloids Surf., B 99: 116-126 (2012). 2. Hiruta, Y, Funatsu, T, Matsuura, M, Wang, J, Ayano, E, Kanazawa, H. 6.8 (Figure 4). The cellular uptake of ID48S10-FL in only weak pH/temperature-responsive fluorescence polymer probe with pH- acidic conditions seems to be because of two factors: 1) controlled cellular uptake, Sens. Actuators, B 207: 724-731 (2015). n hydrophobization of the polymer chains via protonation of the sulfonamidic group, and 2) increasing hydrophobic interactions between the polymer chains and cell membranes. In addition, ID48S10-FL was merged with LysoTracker by utilizing multistaining with LysoTracker, and Hoechst 33342 and ID48S10-FL were merged with LysoTracker. These results indicated that ID48S10-FL might be internalized by HeLa cells, by way of endocytic pathways into the lysosomes.

Figure 4. pH-dependent cellular uptake as shown by fluorescence microscopy images of HeLa cells incubated with ID48S10 at pH 6.8 or 7.4. Green: ID38S10; blue: Hoechst 33342; and red: LysoTracker.

11 Scientifically Speaking

In Situ-Gelling Hydrogels for Ophthalmic Drug Delivery Using a Microinjection Device

Scott B. Campbell, Jun Yang, P. Ravi Selvaganapathy, and Todd R. Hoare McMaster University, Canada

The primary causes of vision loss in developed nations are Hydrogels are a potential solution to this issue, because they related to diseases of the posterior eye (age-related macular can facilitate prolonged delivery of a drug to the eye and limit degeneration, diabetic retinopathy, posterior uveitis, retini- the number of required injections for effective treatment. tis due to glaucoma, etc.).1,2 However, this is a particularly Our research group has developed injectable, degradable difficult target tissue because of anatomic and physiologic hydrogel-based materials for ophthalmic applications that limitations, resulting in few intravitreal treatment options could prolong drug release and have highly adjustable proper- being available. Intravitreal injections have been the preferred ties (swelling, refractive index, gelation time, and API uptake option because they are a facile, direct method of delivering and release). The hydrogels utilize the rapid chemical reac- therapeutic or delivery systems. Unfortunately, to maintain tion of hydrazide-functionalized and aldehyde-functionalized therapeutic levels frequent injections are typically required, polymers to form hydrolytically degradable hydrazone bonds which greatly increases the risk of complications over time that are the basis of the crosslinks in the hydrogel structure and is inconvenient and uncomfortable for the patient.2 (Figure 1).3

These materials have also shown promising in vitro results in many cases, including a hydrogel that does not swell after injection that also matches the refractive index of the vitre- ous humour. However, assessing the in vivo characteristics of these materials is difficult because these experiments re- quire injections in the range of 1–5 μL (and up to 10 μL for humans). While this is facilely done with single component systems, no suitable system exists for the administration of in situ-gelling hydrogels at such low volumes. Furthermore, sin- gle-component microliter-scale syringes cannot be used with these materials because the in situ-gelling nature of these hydrogels is much too rapid to be used with such devices.

The proposed system design should (1) effectively mix the two precursor polymers from separate channels upon injec- tion; (2) controllably and precisely inject volumes in the 1–10 μL range through a narrow-gauge needle suitable for oph- thalmic applications; and (3) rapidly inject these materials to prevent gelation and blockage within the needle. Addition- ally, surgeons want the device to be ergonomical, the injection Figure 1. In situ-gelling system to create hydrogels and microgels. process to not be too rapid (surgery times may vary from 1 to

Figure 2. (A) Macroscale double barrel syringe (left) and the microfluidics-based microinjector device design, highlighting the volume-control reservoir with the associated one-way valve (right), and (B) the polydimethylsiloxane-based device itself. 12 5 min), and for the operation to be as similar as possible to barrels of a double-barrel syringe and attaching that syringe the current method (summarized in the box below). to the two polymer solution inlets, and the mixed fluids can be pushed through to the needle. The needle can then be in- serted into the eye, and an ejection syringe can be compressed to only eject the volume of mixed polymer solution in the volume-control region, because of the one-way valve that is present. The volume-control region can be designed to be of any volume from 1 μL to 5 mL.

Mixing fluids within microfluidic channels is inhibited by the fact that fluid flows at microfluidic scales are laminar in nature. The addition of herringbone grooves was found to dramatically improve the degree of mixing within the chan- nels of preliminary device prototypes, creating microvortexes The microinjector was designed to operate analogously to and allowing for nearly complete mixing only a short distance this macroscale system, which involves a double-barrel sy- (1.75 cm) from the point where the two separate solutions ringe that has solutions of hydrazide-functionalized polymer first interact within the channels. (polymer A) and aldehyde-functionalized polymer (polymer B) in separate loading barrels (Figure 2A). Upon injection, With the volume-control chamber and the one-way flow these two solutions interact in the mixing channel and needle, valve, the device is able to eject droplets with controlled forming the hydrazone bonds that crosslink the polymer to volumes (± around 10%) in the range of interest (1–10 μL) form a hydrogel. via an entirely handheld operation, requiring no additional equipment. The entire volume of the material can be ejected The microinjector design (Figure 2B) consists of two separate from the device, as indicated by using fluorecently labelled inlets that a double-barrel syringe can be connected to, a ser- polymers and observing the volume-control reservoir before pentine mixing channel with herringbone grooves (developed and after the ejection of a 2 μL sample of gel (Figure 3). by Strook et al.)4 to promote mixing, and a volume-control These microinjectors can produce hydrogel droplets from reservoir with a one-way valve coupled with a second syringe multiple combinations of reactive polymer solutions. These input port that can be used to eject the mixed polymer solu- hydrogels can be ejected from devices with 33G needle out- tions out the needle (into the eye). The device is operated lets and smaller capillary outlets (prefered in order to lower by placing the two reactive polymer solutions in separate the overall cost of the devices) into various materials, includ- ing bovine vitreous humour at 37°C (Figure 4).

This microinjection device has proven capable of injecting precise small amounts (1–10 μL) of in situ-gelling hydrogel precursors, which allows for the in vivo assessment of injectable hydrogels as ocular drug delivery materials, which will be available shortly. The hydrogels that this device can deliver to the eye could provide significant improvements over current therapies in terms of treating diseases of the posterior eye. Figure 3. Fluorescent imaging fluorescein isothiocyanate–labelled polymers References before and after pumping out. 1. Myles, ME, Neumann, DM, Hill, JM. Recent progress in ocular drug delivery for posterior segment disease: Emphasis on transscleral iontophoresis, Adv. Drug Delivery Rev. 57: 2063-2079 (2005). 2. Sheardown, H. Critical role for drug delivery in the development of new ophthalmic treatments, Future Med. Chem. 4: 2123-2125 (2012). 3. Patenaude, M, Hoare, T. Injectable, degradable thermoresponsive poly(N-isopropylacrylamide) hydrogels, ACS Macro Letters 1: 409-413 (2012). 4. Stroock, AD, Dertinger, SKW, Ajdari, A, Mezić, I, Stone, HA, Whitesides, GM. Chaotic mixer for microchannels, Science 295: 647-651 (2002). n Figure 4. (A) 2 μL gelled hydrogel droplets in paraffin oil, and (B) dyed blue in bovine vitreous humour at 37°C

13 Patent Watch

Patent Watch

Charles Frey, Coating Place, Inc., U.S.A.

This article briefly summarizes novel aspects of selected U.S. patents involving controlled release or delivery that were issued from January 1 to June 30, 2014. Selections have been loosely categorized into interest areas; however, many overlap into multiple categories. Greater detail on each can be found on the U.S. patent website at http://patft.uspto.gov/.

Abuse Deterrent U.S. patent 8,628,797 – Release rate of poorly soluble bioactives U.S. patents 8,685,447 and 8,691,270 – A super-absorbent is such as clarithromycin in a tablet is controlled by the viscosity incorporated into a coating layer as an abuse deterrent to swell differential of tableting polymers while eliminating or and retard release of analgesic when crushed and exposed to minimizing food effects. aqueous media. Complexes

U.S. patent 8,685,916 – Controlled release of an opioid is U.S. patents 8,709,500 and 8,747,912 – Anionic drug molecules achieved by enzymatic cleavage, which can be modulated with a are intercalated into layered double hydroxides for controlled oral trypsin inhibitor. delivery.

U.S. patent 8,623,412 – Waxes are applied both as a particle coat- U.S. patent 8,734,652 – Porous metal organic frameworks of ing and tableting matrix to control release of analgesic materials. Al-fumarates are described for use as controlled release of guest The resulting matrix limits extractability of the analgesic to less materials. than 15% of the immediate release therapeutic level. U.S. patent 8,680,202 – Cyclodextrin-containing polymers are Agriculture described as drug carriers for controlled delivery of therapeutics. U.S. patent 8,741,804 – Coated magnetic nanoparticles are Devices/Implants covalently bound to the shell of microcapsules of agricultural interest to control microcapsule shell rupture with a magnetic U.S. patents 8,647,657 and 8,722,078 – A copolymerized, field. biodegradable blend of poly-lactide/glycolide or the like and a poly-alkyleneneglycol are coextruded with API for sustained U.S. patent 8,679,546 – A ruminant feed pellet consisting of a release of the API. matrix core containing active substances and multiple coat layers is described for controlled release of the actives. U.S. patent 8,715,707 – A freeze-thaw temperature cycle is used to modify release properties of a stent coating. U.S. patent 8,756,862 – A structurally stable substrate with interconnecting pores is constructed of composted bark, a U.S. patent 8,658,195 – A polyurethane membrane is applied to carbon-based fibrous material, a hydrophilic polymer, sea solid, implantable reservoir devices to control drug release. beneficial bacteria/fungicide, and a controlled release fertilizer to provide an optimum combination of nutrients, water retention, U.S. patent 8,758,428 – A stent coated with a coating layer, and pest and fungus control. bioactive material layer, and vapor deposited polyamide or parylene layer is used to control bioactive material release. U.S. patents 8,741,021 and 8,741,022 – A variation of sulfur- coated urea including an in situ polymerized or thermoset U.S. patent 8,709,467 – A microfilm device consisting of a para- polymer layer provides robust, economically viable controlled zylylene membrane is disclosed for controlled bioactive delivery. release nitrogen sources. U.S. patent 8,628,798 – Water-swellable linear polyurethane Antibiotics polymers capable of swelling 300–1,700% for controlled release U.S. patent 8,758,804 – A gum-like device/composition for of high-molecular-weight bioactives are disclosed. sustained delivery of rifaximin to surfaces in the mouth and similar cavities is disclosed. U.S. patent 8,623,399 – Microminerals impregnated in a porous silicon subcutaneous implant are released over a period up to a U.S. patent 8,748,447 – Extended oral release of rifaximin is year via complete corrosion of the implant or breaching of achieved in a spray-dried powder form. bioerodible doors.

14 U.S. patent 8,679,094 – Intravesical devices that can be U.S. patent 8,652,506 – Block/graft arrangement in implanted in the bladder for controlled drug release within the biodegradable block co-polymers is used as a means to control bladder are disclosed. drug release.

Fragrances U.S. patent 8,632,798 – Cereal β(1-3) β(1-4) glucan is used as a U.S. patent 8,715,702 – Fragrance/surfactant compositions are coating for controlled delivery of pharmaceutical, medical, or encapsulated in 30 µm polymerized tetraalkoxysilane shells for confectionery agents in the mouth. controlled release in fabric softeners, hair conditioners, and the like. U.S. patent 8,722,067 – Ultrasonication is applied to speed silk fibroin gelation to produce a hydrogel controlled delivery matrix. U.S. patent 8,685,425 – Coacervate microcapsules possessing Lewis acid–Lewis base salt walls are used to control release of a U.S. patent 8,734,850 – Orally delivered drug release is water-immiscible core, such as insect repellent or fragrance. controlled with a two-coat configuration consisting of an inner layer containing a swell agent and an outer enteric layer. Injectables U.S. patent 8,691,275 – A solubility-enhancing localized pH U.S. patent 8,734,852 – Injectable formulations of aceclofenac condition is maintained through the digestive tract in an oral and/or diclofenac with immediate and up to 72 hours of controlled release melatonin formulation. sustained release are described. U.S. patent 8,668,954 – An extrusion of mineral particles and U.S. patent 8,722,679 – A freeze-dried injectable aripiprazole binder forms porous granules for incorporation and controlled formulation is disclosed for sustained release for a period up to release of algaecide. eight weeks. Miscellaneous U.S. patent 8,754,190 – Drugs are bound to macromolecular carriers via linker functionalities whereby drug release is U.S. patent 8,715,478 – This invention provides a means to controlled by beta-elimination. electrically control ion transport for physiological process control in cells. Osmotic Systems U.S. patent 8,703,193 – Osmotic tablets are described for U.S. patent 8,629,098 – Modular artificial antigen-presenting controlled release of venlafaxine or metoprolol using controlled cells are described for controlled cytokine release. porosity coatings without a drilled hole.

U.S. patent 8,709,481 – Biodegradable polymers are used with U.S. patent 8,679,534 – An osmotic tablet consisting of a water- acid-sensitive API complexes for controlled delivery up to 18 insoluble coating with an enteric pore former is described for days. controlled release of cholesterol reducing agent. U.S. patent 8,703,907 – Covalently bound drugs are released Proteins/Peptides from dendrimers through controlled beta elimination. U.S. patent 8,623,345 – Polymer-insulin conjugates for U.S. patent 8,697,117 – A freeze-dried, inverted emulsion controlled release of insulin in response to increased glucose formulation is used to create polymeric films for controlled concentration are described. release in physiological fluids. U.S. patent 8,642,082 – Controlled release oral compositions of U.S. patent 8,652,378 – Processes and formulas for creating heparin are described. uniform thin films of taste-masked bioactives for oral delivery Transdermal are described. U.S. patent 8,747,889 – A transdermal controlled delivery system U.S. patent 8,691,272 – A trilayer controlled release tablet for fentanyl with abuse deterrent features consisting of drug and consisting of a drug-containing, nonerodible core sandwiched antagonist reservoirs is described. between two release modulating layers is described. U.S. patent 8,696,637 – A transdermal microneedle assembly U.S. patent 8,674,132 – This invention involves location and patch is disclosed. n nature of modulating substituents to control release of HNO from N-hydroxylsulfonamide derivatives for treatment of heart failure and the like.

15 Special Feature

How to Be a Scientist and yet Write a Literary Novel

Gregory Gregoriadis,1 University College London School of Pharmacy, United Kingdom

I have a confession to make: I have Until one day, the day I saw my lab to be my orchestra and the written a novel, a work of fiction. It has players. It was there, in my room, waiting for me. A table, a pad been just published. “Oh, I see,” you may of A4 paper, and a fountain pen. I had seen my crucible of say. “You were a scientist and now you are thoughts, of creation. I would write a story, a long one. I would an arty person. A high-brow bohemian be king again. And, oh boy, did I have a story to tell! I had been engrossed in dreams and fairy tales, dreaming of it since the time of my teens. A story of things that dancing on clouds.” “Yes,” I would reply, happened to me and to my friends, my family, and neighbours, but, mindful of my academic record being to all of us Athenians. In the shadow of the Parthenon, where blemished, I would add hurriedly. “I am we lived, under the Acropolis. I remember sitting down, a still a scientist, you know. I publish the virginally white sheet of paper waiting to be relished, a pen odd review, articulate a comment here raring to have its ink shed on paper, creating the words and the and there, disagree in silence with sentences. Stories of Mussolini and Hitler, of the Nazis on top someone’s assertions. In silence, because of us, the executions and the great famine. Of corpses in the of my inability to use a flask or a pipette, or to prepare a drug streets. Stories of pathos and Eros as we listened to the cicada solution. Because I can’t inject a rat, observe its reaction, and song. I wrote and wrote, forgetting myself and the world, then hopefully prove my point. You see,” I would go on bitterly, “I do stopped to refill my fountain pen. I read the lines and the not have a lab to test my ideas. I have no affiliation either, just an paragraphs, page after page, horror after horror. This was not a emeritus at University College London. I am no longer king, literary novel! Cold sweat bathed my face. What had I done? head of something. Only of myself. I am retired, a superannuated What a literary disaster. A series of disgusting, languor-dripping has-been.” sentences. The scientist in me had woken up from his stupor, spewing chunks of a Results and Discussion–like text, logically Alas, I can no longer direct others. I have no orchestra, no violins composed, expectorations of accuracy and common sense and cellos, trombones and clarinets. My concert hall is empty, the masquerading as a literary novel. It was a monstrous text. I kept piano smothered by spider webs. Only ghosts of players, slowly writing, desperate to free myself from the shackles of scientific fading in the mist of my receding memory. I would listen to the rationale, of cause and effect. Escape from the lexicon of irksome “Ridi Pagliaccio” threnody on the gramophone and sigh in entries, of sterile sentences studded with pretentious epithets: “in despair, “It is not fair.” Yes, grossly unfair because, after all these conclusion therefore and on the basis of mellifluous statistics, years of science, of publications and conferences, my creativity the Nazis had murdered our heroes.” Or, “he thought of the is still alive and kicking, violently in fact. Yet I have been scrumptious results obtained under controlled conditions, and condemned to paralysing inaction, to ever-decreasing years concluded the famine had killed her.” The paper basket by my of boredom and decay, soon to be forgotten. Some may still side overflowed with screwed up pages of aborted literary feats. remember me, vaguely perhaps, wondering whether I am still around, googling for my obituary. I know because I have done it myself more and more recently. It was there, in my room, Thinking of my future, the dead end of it, has not been easy. One after the other, well-meaning colleagues lacerated me with the waiting for me. A table, a pad of promise of horticulture, the martyrdom of a kitchen garden, of A4 paper, and a fountain pen. tomatoes, leeks, and courgettes. “But,” I would protest, remembering another retired colleague, “didn’t so-and-so take up And as I sat there by the paper basket observing the ruins, my gardening and pay for it? Didn’t he drop dead in the midst of his wasted hours, the never-ending labour of Sisyphus, wondering cabbages?” “Well, he tried to pull out an enormous turnip with his whether I should revisit the dreaded gardening, philately, and bare hands, didn’t he?” said the well-meaning colleagues. Others, boats of pleasure, I rebelled. “No, my friend!” I said to myself in wiser perhaps, would suggest philately. “Invest in stamps,” they anger, my scary cry reverberating within my room. “You’ve got to said, “look at it long term.” What long term? I thought, and change your ways, forget the trodden paths of scientific writing, shivered. I had been transferred to my childhood, the the soulless patent-speak. This is fiction, my friend. You are in abomination of stamp collecting. In my private moments I even control, total unmitigated control.” There was a little silence. toyed with travel, blood-curdling memories coming into me of “Total control? Really? Isn’t this too good to be true?” I asked. boats of pleasure packed with fun-loving oldies. Peregrinating the Then the scary voice again: “Yes, total control, you dummy. You oceans with them, an invisible dead soul among many. can lie ad nauseam, experiment on storytelling, create your narrative, be another Homer. Choose words never seen in a 1 E-mail: [email protected] science paper, produce your own results, modify them, and then 16 adjust them to suit your needs, your plot. You are a master of marionettes, the controller of their moves, their moods and utterings. You can give them life then take it away. You can turn Welcome New them into heroes, a latter-day Odysseus, merciless assassins, a tempestuous Circe. You decide. You are the god Zeus and the CRS Members goddess Athena of the world you have created. But remember, my friend, should your endeavours take you to mixing history Mohammad Ali Amini Russell B. Melchert with fiction, stick to the truth, the scientific facts. Spread the Ana Beloqui Tianxin Miao facts wisely among the scenes of horror, of death and love Abhijit Bhattacharya Abayomi Tolulope and passion. Be a Thucydides.” I had listened to the voice, Giovana Celli Ogunjimi mesmerised. It all sounded so exciting, so liberating. A solitary Shuo Chen Gorka Orive tear had exited the corner of my eye. I heard my voice, a throaty Basawaraj Chickmath Juntang Shao murmur: “I will write a real novel. I will.” Don Enns Sam Shefer Weiwei Fan Scott A. Stelting Gregory Gregoriadis’s book Still the Cicadas Sing was published by Rahela Gasparac Chiaki Takahashi Matador in early 2015. He is a professor emeritus at University Rania Hathout Hengmin Tang College London and the founder of Xenetic Biosciences Inc. He Mary Joseph Sachin Sunil Thakur introduced liposomes (1971) and polysialic acids (1991) in drug and Mibin Kuruvilla Joseph Liang Yang vaccine delivery and has published extensively on the subject. Gregory Heejin Lee Zhanguo Yue Gregoriadis was the director (1981–1999) of the NATO Advanced Jason Li Quanlei Zhu Study Institutes “Targeting of Drugs” and “Vaccines.” He was the Dongfei Liu founder (1978) of the “Drug Carriers in Medicine and Biology” Gordon Research Conference series and, since 1990, chair of the “Liposome Advances” conferences. He has received numerous awards, including the CRS Founders Award (1994), and is a CRS Fellow. n

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17 Chapter News

CRS New Zealand Local Chapter (NZCRS) Events in 2014

Mimi Yang1 and Sharan Bobbala2

“Controlled Release in Response to Environment” was the biopolymers and conducting polymers) with biomedical theme of the 2014 NZCRS Workshop, November 24–25 at the applications in controlled release and tissue engineering. Greg University of Auckland, which was jointly hosted by the New Walker (School of Pharmacy, University of Otago, NZ) presented Zealand and Australian CRS Local Chapters. Invited speakers the interesting utility of electrospinning in agricultural explored applications of controlled release in agriculture, wildlife, applications and demonstrated that it is indeed possible to and animal health. electrospin an entire potted plant!

The session “Agriculture and Environment Controlled Release” Another breakout session with the translational topic of commenced with plenary speaker Charles Frey, principle scientist laboratory to field challenges discussed issues and challenges in at Coating Place (U.S.A.), who discussed the Wurster fluid bed this area, and insightful advice was given by our many experts, and related coating technologies and their applications in including industry delegates from Ballance Agri-Nutrients. agricultural and environmental formulation research, including the need for taste masking, enteric delivery, sustained release, and Postgraduate student attendees were given a three-minute time delayed release. Continuing this theme, Craig Bunt from slot to talk about their research with the aid of one PowerPoint Lincoln University (NZ) discussed important insights into slide to highlight their poster. Interesting projects and hypotheses microbial formulations and toxin delivery for pest and wildlife were brought forth in many disciplines of controlled drug control. Ben Boyd (Monash University, Australia) discussed delivery. Arnold Lee (School of Pharmacy, University of Otago, his research on “Nanostructured Emulsions for Agricultural NZ) was the winner of the postgraduate student prize at the Chemical Delivery—Formulation to Field.” completion of this session.

An excellent conclusion to the day was a tour of the University of Auckland School of Pharmacy laboratories, where students were given the opportunity to show the guests the research facilities.

The theme of the third and final session of the workshop was “Wildlife and Livestock Controlled Release,” which began with Lee Shapiro from Connovation Ltd. (NZ), who discussed regulatory obstacles involved with registering vertebrate toxic agents in New Zealand. Per Wessman (Innovative Farm Systems, AgResearch Ltd., NZ) continued discussions on agricultural applications of controlled release with his talk on “Microbial Formulations for Agriculture: Targeted Delivery and Controlled University of Otago participants who travelled to Auckland for the NZCRS Release of Beneficial Micro-organisms.” Charles Frey followed Workshop. Left to right: Arnold Lee, Siddarth Matikonda, Sasi Yarragudi, with his talk on “Controlled Release Coating Technologies for Greg Walker, Katrin Kramer, and Sharan Bobbala. Animal (and Human) Applications – Taste Masking, Improved Stability, and Improved Delivery,” in which he discussed A breakout session opened the floor to delegates to briefly processes, materials, and strategies of film coating to successfully describe their research. Postgraduate students were invited to achieve controlled release. Kate Wilson from James & Wells raise any issues they had in their experiments, and industry (NZ) discussed intellectual professionals and academics offered advice or research directions. property and gave the This strategy was effective to introduce attendees to each other audience tools to identify and enabled the identification of individuals with specific skills potentially valuable aspects or knowledge. of their work and steps to ensure maximum The second session, “Targeted and Active Controlled Release,” opportunity. opened with Darren Svirskis (School of Pharmacy, University of Auckland, NZ), who introduced us to controlled drug release The 2014 NZCRS from non-biodegradable materials including stimuli-responsive Workshop was highly delivery systems. Javad Foroughi (Intelligent Polymer Research informative and thought Institute, University of Wollongong, Australia) discussed his provoking, as well as research in the development of novel nanofibres (both Mimi Yang and Dedeepya Uppalapati excellent exposure of research (University of Auckland) ready to 1 School of Pharmacy, University of Auckland. for postgraduate students welcome delegates for the 2014 2 School of Pharmacy, University of Otago. involved. NZCRS Workshop. 18 The 4D Conference – Devices for Diagnostics and Drug Delivery – was a joint conference of the Formulation and Delivery of Bioactives (FDB) research theme of the University of Otago, the Consortium for Medical Device Technologies (CMDT), the Centre for Delegates at the D4 conference, which took place at Hutton Theatre, Otago Museum, Dunedin, New Zealand. Photo by Len Bioengineering and Nano- Stevenson. medicine, and NZCRS.

The opening presentation was given by David Grainger concept of fluid jets for needle-free delivery through the skin (University of Utah, U.S.A.) on improving the performance of and the ability of these devices to extract fluids from the diagnostic devices and combination medical devices. Prof. injection site. Shyamal Das (University of Otago, NZ) discussed Grainger quoted several commercial examples to support the the application of spray-dried powders in pulmonary delivery. common problems and technical approaches currently underway Chuck Frey’s presentation emphasized the evolution of coating for these devices. Abraham Rubinstein (University of Jerusalem, equipment and different formulation strategies employed in Israel) addressed in situ diagnosis and screening of early coating. Rapid-fire oral presentations of posters from the malignancy in the gastrointestinal tract by using novel targeted postgraduate students concluded the session with three-minute delivery vehicles. David Budgett (Auckland Bioengineering bursts of enthusiasm. Institute, NZ) spoke on monitoring of intracranial pressure in traumatic brain injury patients. He explained challenges On the second day, Stewart Jessamine (Medsafe, Wellington, associated with a brain pressure monitoring device in NZ) discussed the regulatory concerns in translation. Anand development and regulatory stages. Rajesh Katare interpreted the Kumble (Pictor, importance of circulating microRNAs as biomarker for the early Auckland, NZ) engaged diagnosis of all the audience cardiovascular by describing his disease in people experiences in translating with diabetes. an expensive lab ELISA Stephen Sowerby technique to a low-cost (University of immunodiagnostic for Otago, NZ) gave different diseases. Craig insight into a simple Bunt demonstrated portable digital application of 3D microscopy system printing in developing developed in their drug delivery and NZCRS president Arlene McDowell awards Invited speakers at the D4 Conference. Left to lab for imaging medical devices by the NZCRS speaker prize to Sharan Bobbala. The title of Sharan’s presentation right: Azim Ali, Andrew Taberer, Stephen parasite ova in stool showing some interesting was “Novel Injectable Pentablock Copolymer Sowerby, Anand Kumbble, David Grainger, videos. Azam Ali samples and their Hydrogels for Sustained Release Cancer Stewart Jessamine, David Budgett, Ben Boyd, importance in (University of Otago, James Birchall, Quentin Pankhurst, Chuck Frey, Vaccines.” Photo by Rohit Jain. monitoring NZ) spoke on translation and Shyamal Das. Photo by Len Stevenson. antihelminthic drug of biomaterials into devices. George Dias (University of Otago, efficacy. Ben Boyd concluded the session with a talk on NZ) gave a stimulating talk on usage of a resorbable keratin- development of self-assembled lipid systems as new design based biopolymer in bone-regeneration scaffolds. The session elements for diagnostic systems. ended with a motivating presentation from David Powell (Lost Ark Discoveries, NZ) on U.S. medtech innovation and lessons James Birchall (Cardiff University, U.K.) spoke on microneedle learned from it. devices for drug and vaccine delivery through skin. His explanation on microneedle usage in targeting the skin immune The final session of day two comprised oral presentations cells for the treatment of diabetes was the highlight. Another covering different research areas from postgraduate students and interesting aspect on health care biomagnetics was introduced to postdoctoral fellows from New Zealand and Australia. After oral the audience by Quentin Pankhurst (University College London, presentations, Arlene McDowell (NZCRS President) announced U.K.). He described magnetic nanoparticles’ role in targeting and the NZCRS speaker prize winner for 2014: Sharan Bobbala n activation for the controlled release technology. Andrew Taberner from the School of Pharmacy, University of Otago. (Auckland Bioengineering Institute, NZ) presented a novel 19 DDTR Updates

Drug Delivery and Translational Research (DDTR)

Vinod Labhasetwar, Editor-in-Chief, Cleveland Clinic, Cleveland, Ohio, U.S.A.

In the last issue of the CRS Newsletter, I of expertise, please contact me (Vinod Labhasetwar, labhasv@ccf. highlighted the “impact of negative data” org) with a proposed topic and outline. A special issue on tissue and DDTR policy. In the upcoming issue engineering, guest edited by Sing Yian Chew of Nanyang of DDTR, you will see an editorial on the Technological University, Singapore, and Kam W. Leong of same topic. DDTR will consider Duke University, U.S.A., will be published as the March/April publication of studies that are based on a issue of DDTR. strong scientific rationale, hypothesis, or technology but resulted in a negative or Call for Papers unexpected finding. Authors are strongly DDTR is currently accepting submissions for three special issues: Vinod Labhasetwar encouraged to discuss in the manuscript • the possible reasons why experiments “Microneedles for Drug and Vaccine Delivery and Patient failed and what alternative approaches or changes to the Monitoring,” which will showcase emerging pharmaceutical, hypothesis or experimental design might be made. engineering, and formulation approaches to manufacture of microneedles, while also looking at their applications in drug In this regard, I wish to highlight an article published in the and vaccine delivery and minimally invasive patient current issue of DDTR by McConville et al., titled “Lack of In monitoring and diagnosis. Topics include gene/drug delivery Vitro–In Vivo Correlation for a UC781-Releasing Vaginal Ring systems, vaccine delivery systems, and material design and in Macaques,” which falls into the above category. This study production, with a strong focus on clinical translation and describes the preclinical development of a matrix-type silicone commercialization. Guest editors are Ryan Donnelly elastomer vaginal ring device designed to provide controlled ([email protected]) and Dennis Douroumis release of UC781, a non-nucleoside reverse transcriptase ([email protected]). inhibitor. Testing of both human and • “Orthopedic Biomaterials and Drug Delivery,” which will macaque-sized rings in a sink feature emerging pharmaceutical and regenerative approaches condition in vitro release model to treat injuries, diseases, and disorders of the musculoskeletal demonstrated continuous UC781 system. Topics include gene/drug delivery systems, cell-based release in quantities considered therapies, and biomaterials to support orthopedic tissue sufficient to maintain vaginal fluid regeneration and/or disease modification. Please contact guest concentrations at levels 82- to 860- editors Blanka Sharma ([email protected]) and fold higher than the in vitro IC50 Shyni Varghese ([email protected]). (2.0–10.4 nM) and therefore • potentially protect against mucosal “Recent Advances in Dermal Delivery of Therapeutics,” which transmission of HIV. The 100 mg will showcase articles encompassing emerging approaches to UC781 rings were well tolerated in delivering therapeutic agents. Topical products have been one pig-tailed macaques, did not induce of the major conventional modes of delivering pharmaceuticals. local inflammation as determined by cytokine analysis, and The nature of vehicles used in topical delivery of therapeutics maintained median concentrations in vaginal fluids of UC781 in has undergone significant evolution. Please contact guest editor the range of 0.27–5.18 mM during the course of the 28-day S. Narasimha Murthy ([email protected]). study. Analysis of residual UC781 content in rings after completion of both the in vitro release and macaque DDTR Outstanding Research Paper Award pharmacokinetic studies revealed that 57 and 5 mg of UC781 Consider submitting your best research for the 2015 DDTR were released, respectively. The pharmacokinetic analysis of a 100 Outstanding Research Paper Award. The paper will be selected mg UC781 vaginal ring in pig-tailed macaques showed poor in from the research articles, clinical research, and clinical trials vivo–in vitro correlation, attributed to the very poor solubility of published in DDTR during 2015 and will be presented during UC781 in vaginal fluid and resulting in a dissolution-controlled the 43rd CRS Annual Meeting, July 17–20, 2016, Seattle, drug release mechanism rather than the expected diffusion- Washington, U.S.A. Visit the CRS website for award criteria. controlled mechanism. Free Access for CRS Members DDTR Special Issue on Tissue Engineering Visit the DDTR website to glance through research articles, reviews, editorials, and special issues published in DDTR. CRS DDTR has published 10 high-impact special issues and is members receive free access to the online journal content as a currently developing a few more for publication in 2015–2016. membership benefit. Login to the CRS website first, and then If you are interested in developing a special issue in your area click the Publications tab to get to the member access link. n

20 AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE People in the News

Compiled by Steven Giannos, Independent Consultant

Ph.D., the former chairman and CEO of Celgene Corporation Congratulations to Robert Langer for whom the award is named. “Based on the innovative of the Massachusetts Institute of technology of PEGylation that he helped pioneer, Abe founded Technology on receiving the Queen one of the first successful biotech companies in the state. His Elizabeth Prize for Engineering, vision for the industry helped drive the formation of BioNJ as its which includes a £1 million award. founding chairman and through his leadership he continues to foster research into areas that have the potential to benefit Langer runs one of the largest millions of patients around the world.” academic laboratories in the world, is the most cited engineer in history Dr. Abuchowski is currently the CEO and CSO of Prolong (170,000 times), has more than 800 Pharmaceuticals. Research at Prolong is concentrated on finding patents granted or pending, and has co-founded over 20 treatments for anemias, cancers, and their debilitating companies. His connections with CRS include belonging to comorbidities. A portfolio of hematology and oncology products the CRS College of Fellows, being a past president of CRS that use PEGylation technology is in development. Located in (1991–1992), and receiving the Founders Award (1989), and South Plainfield, the company announced in December 2014 that many prominent CRS members are connected in some way it was doubling its manufacturing operations to 24,000 square to the Langer Lab at MIT. feet and relocating to a new 12,000 square-foot headquarters.

The award credits him with improving more than 2 billion The development of PEGylation was part of his 1981 doctoral lives worldwide through disease treatments created in his thesis at Rutgers University, which earned him the moniker “the lab. Langer is known for bringing together researchers from father of PEGylation.” In 1983, Dr. Abuchowski left Rutgers to many different disciplines, and this interdisciplinary develop PEGylation commercially by founding Enzon, Inc., as a approach is central to CRS and to our members’ work. spinout from the university. Enzon was the first biotechnology company in New Jersey to obtain FDA approval of a product. Enzon’s first milestone drug was ADAGEN, the uses of which Father of PEGylation to Receive Dr. Sol J. Barer Award at included the treatment of severe combined immunodeficiency Gateway Gala, BioNJ’s 22nd Annual Dinner Meeting, (SCID), a rare genetic disease of metabolism that is also known as Networking Event and Innovation Celebration “bubble boy disease.”

Business Wire: January 13, 2015 – TRENTON, NJ, U.S.A. – In addition to his groundbreaking work with PEGylation, Abraham Abuchowski, Ph.D., considered the father of Dr. Abuchowski played a pivotal role in the creation and PEGylation, the most widely used protein drug delivery system development of BioNJ, which was formerly known as the in the world, which has helped save and improve thousands of Biotechnology Council of New Jersey (BCNJ). lives, including many with “bubble boy disease,” will be honored with the 2015 Dr. Sol J. Barer Award for Vision, Innovation, and Dr. Abuchowski was among a group of New Jersey life science Leadership, at the Gateway Gala, BioNJ’s 22nd annual dinner executives who recognized the need for an advocacy organization meeting, networking event and innovation celebration on to help the then-emerging biotechnology industry realize its February 5 at the Hilton, East Brunswick, NJ. Dr. Barer will potential to discover and develop new medicines and contribute present the award. to the economy. He was elected as the organization’s first chairman in 1994. PEGylation defines the modification of a protein, peptide, or nonpeptide molecule by the linking of one or more polyethylene “As our founding chairman, Abe’s vision set a direction and tone glycol (PEG) chains. Medicines developed with a PEGylation for this organization that is still having an impact today,” said delivery system have several advantages, including a prolonged Debbie Hart, president and CEO of BioNJ. “I was fortunate to residence in the body, a decreased degradation by metabolic have been involved with Dr. Abuchowski and his colleagues in enzymes, and a reduction or elimination of protein the founding of BioNJ, and it has been an honor and pleasure immunogenicity. Thanks to these favorable properties, from this vantage point to have the opportunity to learn from and PEGylation plays an important role in drug delivery, enhancing work with him and to watch as he continues to help patients and the potentials of peptides and proteins as therapeutic agents. advance the life sciences industry in New Jersey and around the world.” “Dr. Abuchowski has had a long and lasting impact on biotechnology in New Jersey and beyond,” said Sol J. Barer, People in the News continued on page 22 21 AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE

People in the News continued from page 21

The Dr. Sol J. Barer Award for Vision, Innovation, and Leadership in chemistry with a concentration in neuroscience from Oberlin was established by the BioNJ Board of Trustees in March 2008 in College and an M.S. in physical chemistry from Michigan State an effort to recognize the outstanding research and business University. leaders who have made and continue to make significant contributions to the growth of the biosciences in New Jersey and PixarBio Corporation is dedicated to developing new therapeutic around the world. The honoree is voted on by the BioNJ Board of options for Parkinson’s disease, epilepsy, pain, and spinal cord Trustees from a recommendation based on nominations received injury. Cofounded by Frank Reynolds, Dr. Robert S. Langer from by the Nominating Committee. The award is named for Sol J. MIT’s Langer Lab, and Katrin Holzhaus, the company is Barer, Ph.D., who founded the biotechnology group at Celanese developing novel smart materials to achieve sustained release of that was subsequently spun out to form Celgene, one of the agents. Research is focused on a platform for chronic neurological world’s largest biotechnology companies. applications. For more information, visit www.pixarbio.com.

Past award recipients since 2008 have included Dr. Barer; Dr. Lisa PixarBio Cofounder Dr. Robert S. Langer Honored with Drakeman, former president and CEO of Genmab; John H. Prestigious 2014 Kyoto Prize Johnson, then president of global oncology and senior vice Business Wire: November 19, 2014 – MEDFORD, MA, president of Eli Lilly and Company; John Crowley, chairman and U.S.A. – PixarBio Corporation is pleased to announce that its CEO of Amicus Therapeutics; Paul G. Thomas, founder and cofounder Dr. Robert S. Langer was honored with the prestigious CEO of Roka Bioscience; Francois Nader, M.D., president and 2014 Kyoto Prize presented by the Inamori Foundation earlier CEO of NPS Pharma; and Stuart W. Peltz, Ph.D, CEO of PTC this month in Kyoto, Japan. The international award is presented Therapeutics. to individuals who have contributed significantly to the progress PixarBio’s Dr. Jason Criscione Named Director, Drug of science, the advancement of civilization, and the enrichment Delivery Programs and elevation of the human spirit. Dr. Langer received the advanced technology prize in the field of biotechnology and Business Wire: December 3, 2014 – MEDFORD, MA, U.S.A. – medical technology for his work as “a founder of the field of tissue PixarBio Corporation today announced that Jason Criscione, engineering and creator of revolutionary drug delivery system Ph.D., has been named director of drug delivery programs. Dr. (DDS) technologies.” Criscione joined PixarBio in March 2014, bringing his immunotherapy drug delivery and materials science experience to Frank Reynolds, PixarBio’s CEO, said, “For almost a decade I’ve design, develop, and clinically translate biomaterials for sustained, had the honor to collaborate with Bob Langer on important local therapeutic intervention in neurological indications. projects, and he just keeps getting better every year. For decades to come, all of our loved ones will benefit from his inventions, and “Our time-proven R&D model based on concurrent engineering the legions of scientist who follow will marvel at his genius.” will optimize the speed of development of Dr. Criscione’s work.” Other laureates included theoretical physicist Edward Witten, “PixarBio’s founders have translated more products to the clinic honored for his “contributions to the development of mathemati- than any biomaterials researchers in history. I joined the team to cal sciences through the exploration of superstring theory,” and bring immunotherapy approaches to PixarBio, and our early Fukumi Shimura, “an artist in constant pursuit of the fundamen- success in pain justifies optimism for the development of novel tal human value of harmonious coexistence with nature.” treatments for a range of acute and chronic neurological conditions such as Parkinson’s disease, epilepsy, and spinal cord injury. I’ve PixarBio Corporation is dedicated to developing new therapeutic had a great start at PixarBio and now it is time to finish options for Parkinson’s disease, epilepsy, pain, and spinal cord translation to the clinic,” said Dr. Criscione. injury. Cofounded by Frank Reynolds, Dr. Robert S. Langer from MIT’s Langer Lab, and Katrin Holzhaus, the company is “Dr. Criscione has been instrumental in developing our developing novel smart materials to achieve sustained release of postoperative and acute nonopiate pain drug delivery platform. agents. Research is focused on a platform for chronic neurological Jason provides PixarBio with new thought leadership around applications. For more information, visit www.pixarbio.com. novel approaches to pain and a whole range of immune system disorders,” said PixarBio CEO Frank Reynolds. “Our time-proven The Kyoto Prize is Japan’s highest private award for global R&D model based on concurrent engineering will optimize the achievement, created by noted philanthropist Dr. Kazuo Inamori. speed of development of Dr. Criscione’s work.” The Kyoto Prize is awarded annually to persons who have made significant contributions in the three categories of advanced Dr. Criscione received his Ph.D. in biomedical engineering from technology, basic sciences, and arts and philosophy. Through this Yale University. His research focused on designing micro- and prize, the Inamori Foundation seeks not only to recognize nanoparticle platforms to enable intelligent drug delivery and outstanding achievements but also to promote academic and noninvasive, multimodal imaging. His expertise expanded to cover cultural development and to contribute to mutual international chemistry, polymer and materials science, colloid science, understanding. For more information, visit www.inamori-f.or.jp/ spectroscopy, biophysics, and immunotherapy. He also holds a B.A. laureates/k30_a_robert/prf_e.html. n 22 AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE In the News

Compiled by Steven Giannos, Independent Consultant

January “We created a simple, de-risked, and success-based process that Depomed to Acquire U.S. Rights to NUCYNTA® allows for quick decisions and minimal commitment. This allows (Tapentadol), NUCYNTA® ER (Tapentadol) Extended partners to respond to changing markets or strategic plans,” said Release Tablets, and NUCYNTA® (Tapentadol) Oral Dr. Stephen Hsu, CEO of Prometheon Pharma and inventor of Solution from Janssen Pharmaceuticals, Inc., for its technology. $1.05 Billion The collaboration model is a simple fee-for-service contract PRNewswire: January 15, 2015 – NEWARK, CA, U.S.A. – designed to de-risk the development process for pharma/biotech Depomed, Inc. (NASDAQ: DEPO) today announced that it has partners and provide initial results in as few as four weeks. entered into a definitive agreement to acquire the U.S. rights to Prometheon will optimize its proprietary Topicon™ the NUCYNTA franchise from Janssen Pharmaceuticals, Inc., ThermoMatrix™ formulations to deliver target molecules across for $1.05 billion. The NUCYNTA franchise includes a robust and validated human skin model to predict if its NUCYNTA® ER (tapentadol) extended release tablets indicated TruePatch™ product can achieve clinically meaningful for the management of pain, including neuropathic pain bioavailability in patients. associated with diabetic peripheral neuropathy (DPN), severe enough to require daily, around-the-clock, long-term opioid This semi-high throughput model allows the testing of many treatment, and NUCYNTA® (tapentadol), an immediate release drugs simultaneously to establish the dose-response range and version of tapentadol, for management of moderate to severe saturating dose and to conduct tissue toxicology studies. These acute pain in adults. NUCYNTA (tapentadol) oral solution is an deliverables will be owned by the collaborator, who can then approved oral form of tapentadol that has not been launched. choose to progress to small animal studies through fee-for- The deal will make NUCYNTA the flagship asset in Depomed’s service before pursuing a long-term partnership with growing portfolio of pain and neurology specialty Prometheon. pharmaceuticals. Please refer to the summary descriptions below for more information on NUCYNTA and NUCYNTA ER. Full Setting a new industry standard, Prometheon created the first product labeling including boxed warnings for NUCYNTA ER thermosensitive patches that maintain the stability of perishable and NUCYNTA is available at www.Nucynta.com. large-molecule drugs in a solid matrix at room temperature with its Topicon™ ThermoMatrix™ formulation. Upon application to “We believe that NUCYNTA is an ideal strategic fit for the skin, the formulation melts into a dermoadhesive gel, which Depomed—a rare opportunity to add a proprietary, differentiated serves as a drug reservoir that delivers drugs at a constant and drug with a lengthy period of exclusivity that fits precisely into consistent rate. our therapeutic focus,” said Jim Schoeneck, president and chief executive officer of Depomed. “NUCYNTA meets all of our Prometheon has already used its highly versatile platform criteria for product acquisition that we have laid out over the technology in small animal models to deliver large-peptide drugs past two years. The NUCYNTA franchise generated U.S. net such as insulin and human growth hormone, as well as a hair sales of approximately $166 million for the 12 months ended regrowth formula. ThermoMatrix™ patches could also deliver September 2014. NUCYNTA has composition of matter patent many other important small-molecule and peptide drugs, as well protection to August 2022, a potential pediatric extension into as subunit vaccines and gene therapies. 2023, and additional patents that could extend beyond that timeframe. Finally, the synergies between NUCYNTA and our Prometheon Pharma is a biotechnology company housed in the existing pain and neurology call points create a number of globally #1-ranked Sid Martin Biotech Incubator at the opportunities to grow not only the NUCYNTA franchise but to University of Florida. Prometheon is dedicated to increasing enhance the growth of our current business as well.” patient compliance and access as well as reducing healthcare costs with needle-free transdermal, low-refrigeration patches for Needle-Free Transdermal Delivery Startup Prometheon large peptide and protein drugs. For more information, please Pharma Opens Platform to Promote Industry Partnerships visit www.prometheonpharma.com. Business Wire: January 13, 2015 – GAINESVILLE, FL, U.S.A. – As the biotech industry and investors converge on San Francisco for the JP Morgan Healthcare Conference, University of Florida spinoff Prometheon Pharma announced plans to open its needle-free transdermal patch technology platform to promote industry partnerships. In the News continued on page 24

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BioLight Announces New Investment in Development of System, with the support of the UC San Diego Sanford Stem Ophthalmic Drugs Cell Clinical Center and under the direction of principal PRNewswire: January 12, 2015 – TEL AVIV, Israel – BioLight investigator Robert Henry, M.D. The first implant was Life Sciences Investments Ltd. (OTC: BLGTY, TASE: BOLT), performed in October 2014. a firm that invests in, manages, and commercializes biomedical innovations in ophthalmology and cancer diagnostics, today In addition to determining the safety of the product candidate in announced its investment in a newly formed ophthalmic these patients, STEP ONE is designed to evaluate the company that has licensed-in a worldwide drug-delivery effectiveness of the VC-01 product candidate in replacing the platform from the Hebrew University, Israel, that has the lost endocrine function that is central to the disease. In an open- potential to enable more efficient and safer delivery of eye drops. label, dose-escalating format, ViaCyte expects to enroll approximately 40 patients in the study at multiple clinical sites. This drug-delivery platform will help address improving patient compliance with eye disease drug regimens and will form the ViaCyte is a privately held, clinical-stage regenerative medicine basis for possible drug development by the new company company focused on developing a novel cell therapy for the targeting diseases affecting both the front and back of the eye. treatment of diabetes. ViaCyte is conducting a phase 1/2 clinical trial, called STEP ONE, of the company’s lead product BioLight will comanage the new company and will hold 40% candidate, VC-01, in patients with type 1 diabetes who have equity stake. minimal to no insulin-producing beta cell function. The VC-01 combination product is based on the production of pancreatic Suzana Nahum-Zilberberg, BioLight’s chief executive officer, progenitor cells (PEC-01™ cells), which are implanted in a said, “This new investment represents a major step in our goal to durable and retrievable encapsulation device, known as the ® expand our ophthalmic portfolio that addresses clear unmet Encaptra drug delivery system. Once implanted and matured, needs in the multibillion dollar ophthalmic drug market. Our these cells are designed to secrete insulin and other regulatory experience in the ophthalmic space will definitely contribute to factors in response to blood glucose levels. The VC-01 the new company efforts to find the best ways to develop this combination product is being developed as a potential long-term novel drug delivery technology into a portfolio of new drugs diabetes treatment without immune suppression and without with better efficacy and safety profiles.” risk of hypoglycemia or other diabetes-related complications. ViaCyte Receives Clearance from Health Canada for ViaCyte is headquartered in San Diego, California, with Diabetes Clinical Trial additional operations in Athens, Georgia. The company is funded in part by the California Institute for Regenerative Medicine and PRNewswire: January 8, 2015 – SAN DIEGO, CA, U.S.A. – JDRF. For more information, please visit www.viacyte.com. ViaCyte, Inc., a privately held regenerative medicine company with the first stem cell-derived islet replacement therapy for the Covidien’s Stellarex™ Drug-Coated Angioplasty Balloon treatment of diabetes in clinical trials, has received a No Receives CE Mark to Treat Peripheral Arterial Disease Objection Letter from Health Canada providing clearance to Patients proceed with sites in Canada for the company’s phase 1/2 clinical trial of its VC-01™ product candidate. The VC-01 product Business Wire: January 8, 2015 – DUBLIN, Ireland – Covidien candidate is currently being evaluated in patients with type 1 plc (NYSE: COV) today announced it has received CE Mark diabetes who have minimal to no insulin-producing beta cell approval for its Stellarex™ drug-coated angioplasty balloon function. The location and enrollment start date of the first (DCB). The Stellarex™ DCB is used to restore and maintain Canadian clinical trial site have not yet been disclosed. blood flow to the arteries of the leg in patients with peripheral arterial disease (PAD). “The first cohort of patients in this two-cohort dose escalation study of the VC-01 product candidate is currently being assessed The Stellarex™ DCB is inserted into the diseased artery and at a single site in the United States. Should the product inflated to open the vessel and restore blood flow, while a drug candidate proceed to the second cohort, we intend to expand the called paclitaxel is deposited onto the vessel wall to prevent the trial to multiple sites,” said Paul Laikind, Ph.D., president and reoccurrence of new blockages. The Stellarex™ DCB’s CEO of ViaCyte. “Health Canada’s approval represents further proprietary EnduraCoat™ technology provides a durable, validation of the trial and allows us to expand internationally to uniform coating that reduces drug loss during transit and one or more sites in Canada.” facilitates efficient drug delivery to the treatment site.

The Investigational New Drug application for the phase 1/2 trial, According to The Lancet, 40.5 million cases of PAD were called STEP ONE, or Safety, Tolerability, and Efficacy of VC-01 reported in Europe in 2010. PAD occurs when arteries in the Combination Product in Type 1, was allowed by the U.S. Food legs become narrowed or blocked by plaque. These blockages and Drug Administration in August 2014. The STEP ONE trial (lesions) can result in severe pain, limited physical mobility, was launched in September 2014 at UC San Diego Health nonhealing leg ulcers, and leg amputation. Patients with PAD

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also have an associated higher risk of heart attack, stroke and Proportion of subjects that did not require additional death. antimicrobial therapy at the end of the treatment period, the microbial eradication rate, time-to-end of pain, and the disease “PAD is a progressive disease that affects millions of people recurrence rate, all being efficacy parameters, were found similar around the world. DCBs are emerging as an alternative to between FoamOtic Externa and Ciprodex®, the leading traditional treatment options, such as angioplasty or stenting, marketed ear drops for AOE. The overall adverse events (AEs) because of their ability to restore blood flow, prevent the and serious adverse events (SAEs) rates were similar between the reoccurrence of new blockages, and preserve future treatment two treatment groups, indicating a similar safety profile. options,” said Dr. Henrik Schröeder, radiologist, Vascular “FoamOtic Externa is an effective product, easy to use, and was Center–Jewish Hospital, Berlin, Germany, and principal very well accepted by the patients. It enhances patient investigator, Illumenate first-in-human (FIH) study. “In clinical compliance since it is conveniently applied once a day. I will trials, the Stellarex™ DCB has demonstrated promising results definitely recommend using this product based on patients’ with strong patency rates and low reoccurrence of target lesions feedback,” said Dr. Shmuel Gur of Clalit Health Services – at 24 months.” Pediatric Clinic, Kfar-Saba, Israel, an investigator in the study.

The 24 month results of the Illumenate FIH study demonstrated FoamOtic Externa is a proprietary, foam-based extended-release a primary patency rate (ability to keep the artery open to restore formulation of ciprofloxacin antibiotic that has been designated blood flow) of 80.3%. Additionally, the study showed 87.9% for self-applied once-daily administration to treat AOE. freedom from target lesion revascularization at 12 months and 85.8% at 24 months. The FoamOtic platform addresses the inherent limitations of ear drops. The foam expands, providing good coverage of the infected On November 2, 2014, Covidien announced it had entered into area; it does not drip out of the ear and while collapsing provides a definitive agreement with Spectranetics Corporation under continuous release of the active pharmaceutical ingredients. which Spectranetics will acquire Covidien’s Stellarex™ DCB FoamOtic application is fast and easy, does not require tilting the platform. The transaction is subject to the closure of the pending head or lying on the side, can be self-administered, and provides acquisition of Covidien by Medtronic, which is expected to superior convenience compared with ear drops. occur in early 2015. Clinical studies have demonstrated that once-daily Otic Pharma Announces Positive Results from a Phase 2 administration of FoamOtic Externa provides sustained Trial of FoamOtic Externa ciprofloxacin drug concentrations in the external ear canal that Business Wire: January 7, 2015 – REHOVOT, Israel – Otic can successfully eradicate the pathogenic bacteria as with twice- Pharma, a privately held biopharmaceutical company focused on daily dosing of antibiotic ear drops. The lead indication for the development of innovative retained, localized foam-based FoamOtic is AOE in minor and adult patients. The product products for ear, nose, and throat (ENT) disorders, announced candidate completed a phase 2 trial. Otic Pharma is preparing to positive clinical results of its lead product, FoamOtic Externa. A launch in 2015 a pivotal phase 3 study of FoamOtic Externa to single agent, steroid-free product was studied in a phase 2 clinical obtain the clinical data required for its approval by the FDA. trial with 220 minor and adult patients with acute otitis externa Bio-Path Holdings’ Liposomal Grb-2 Featured in (AOE). Once-daily dosing of FoamOtic Externa (ciprofloxacin Peer-Reviewed Journal Expert Opinion on Drug Delivery 0.3% otic foam) demonstrated excellent safety and a similar clinical cure rate as twice-daily dosing of Ciprodex® ear drops Business Wire: January 7, 2015 – HOUSTON, TX, U.S.A. – (0.3% ciprofloxacin and 0.1% dexamethasone otic suspension, Bio-Path Holdings, Inc., (NASDAQ: BPTH) (“Bio-Path”), a Alcon), the world-leading marketed ear drops for AOE. biotechnology company developing a liposomal delivery technology for nucleic acid cancer drugs, today announced that “We are very pleased with these positive results with once-daily data from preclinical studies of BP-100-1.01 (liposomal Grb-2) dosing of FoamOtic Externa. Based on these data, we will be were featured in the peer-reviewed journal Expert Opinion on initiating a U.S.-based phase 3 trial with FoamOtic Externa Drug Delivery. during 2015,” said Orna Palgi, Ph.D., executive vice president of Otic Pharma. “FoamOtic provides good coverage of the infected The paper, titled “Liposomal Delivery of Nucleic Acid-Based ear canal, and the continued release of the drug allows once-daily Anticancer Therapeutics: BP-100-1.01,” was authored by Ana dosing and better compliance, which is a major advantage for Tari, Ph.D., director preclinical operations and research at Bio- kids. Based on the results the company is developing foam-based Path, and Jorge Cortes, M.D., deputy department chair, products for additional ENT disorders.” Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. The review The randomized, multicenter, parallel, comparative phase 2 trial article can be accessed at www.biopathholdings.com/pdf/ enrolled patients aged six months and older. ExpertOpiniononDrugDelivery.pdf.

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Antisense oligonucleotides, siRNA, and anti-microRNA are agents to solid tumors at the optimized drug ratio is expected to designed to selectively bind to target mRNAs and silence significantly enhance the efficacy of this combination. This disease-causing or associated proteins. The clinical development should help establish the broad applicability of the CombiPlex of nucleic acid drugs has been limited by their poor platform in the development of combination cancer therapies. bioavailability. This review article examined strategies that have This patent provides protection until November 2028. been utilized to improve the bioavailability of nucleic acid drugs, particularly the design of cationic and neutral lipid nanoparticles Celator’s nanoparticle-based delivery technology provides that enable the systemic delivery of nucleic acids in vivo and the versatile control of the pharmacokinetics and tissue accumulation proof-of-concept evidence that intravenous administration of of taxanes such as paclitaxel and docetaxel. The patent covers a nucleic acids incorporated into lipid nanoparticles leads to pharmaceutical composition comprising nanoparticles or decreased expression of target genes in humans. micelles, where the nanoparticles or micelles are formed from associating 1) a conjugate of taxane coupled to a hydrophobic The paper featured preclinical studies of liposomal Grb-2 lipid-anchor through a diglycolate linker with 2) a lipid and/or antisense oligonucleotide incorporated into neutral liposomes and amphiphilic stabilizer. The allowed claims may also provide concluded that the drug is a specific Grb-2 inhibitor. Grb-2 is an patent protection for formulations combining docetaxel, and attractive target because, despite not having specific enzymatic other taxanes, with molecularly targeted agents. activity of its own, it serves as a linker to transduce signals from a number of oncogenic proteins that result in the activation of the “By connecting a hydrophobic anchor to taxanes in a manner Ras signaling pathway. Early results of a phase I trial in leukemia that readily incorporates them into stable nanoparticles, we have suggest that liposomal Grb-2 effectively reduces Grb-2 protein been able to reduce early distribution of these drugs to healthy expression, resulting in inhibition of downstream Ras effectors tissues while enhancing and extending their exposure to tumor such as phosphorylated Erk (extracellular signals regulated tissue,” said Dr. Lawrence Mayer, president and chief scientific kinases) at doses that have not resulted in dose-limiting toxicity. officer of Celator. “The improved tumor drug exposure properties Studies with liposomal Grb-2 are continuing and expanding to correlated with increased antitumor activity when compared with other indications as well as combinations to fully understand the conventional formulations of docetaxel at equivalent doses, and role liposomal Grb-2 antisense may have in cancer therapy. the reduced toxicity of the nanoparticle formulation in mice led to marked efficacy improvements when it was dosed at the “The publication of data from our lead compound, liposomal maximum tolerated dose.” Grb-2, in this respected peer-reviewed journal emphasizes the potential importance Bio-Path’s proprietary neutral liposomal Microchips Biotech, Inc., Completes Development and delivery technology may have in oncology,” said Peter Nielsen, Clinical Demonstration of Proprietary Drug Delivery chief executive officer of Bio-Path Holdings, Inc. “As we move Platform and Advances Commercialization Efforts in liposomal Grb-2 through the clinic, we will continue to share our Diabetes, Contraception, and Osteoporosis findings with the medical community through peer-reviewed Business Wire: December 15, 2014 – WALTHAM, MA, publications and conferences, increasing the exposure of our U.S.A. – Microchips Biotech, Inc., formerly MicroCHIPS, Inc., unique technology and drug candidates and expanding our today announced the completion of the development and clinical partnering opportunities.” demonstration of its proprietary drug delivery technology, a December microchip-based implant capable of storing and releasing precise doses of a drug on demand or at scheduled intervals for up to 16 Celator® Pharmaceuticals Receives European Patent years. Unlike traditional drug delivery platforms, Microchips Allowance on Nanoparticle Delivery Technology Biotech’s implant is capable of responding to wireless signals, which can activate, deactivate, or modify the frequency or dose of PRNewswire: December 18, 2014 – EWING, NJ, U.S.A. – the drug without requiring removal. Microchips Biotech is Celator Pharmaceuticals, Inc. (Nasdaq: CPXX), a currently pursuing applications of its platform in three key areas: biopharmaceutical company transforming the science of diabetes, female contraception, and osteoporosis, which all require combination therapy and developing products to improve patient frequent, long-term dosing and high patient compliance. outcomes in cancer, today announced that the application of Microchips Biotech published clinical data demonstrating the European patent number 2,222,278 was allowed by the ability of its platform to deliver a drug to treat osteoporosis in European Patent Office. The new patent, “Improved Taxane women and is actively advancing development and clinical Delivery System,” covers the company’s proprietary taxane research programs in diabetes and female contraception, prodrug nanoparticle-delivery technology and CPX-8, a respectively. hydrophobic docetaxel prodrug nanoparticle, which is based on this innovative approach to drug delivery. Celator is currently “Innovating drug delivery is an integral complement to drug applying its proprietary CombiPlex technology to drug discovery, and Microchips Biotech is uniquely poised to combinations incorporating targeted agents, such as a revolutionize the way medicines are administered on a long-term combination of docetaxel with a heat shock protein (Hsp90) basis,” said Cheryl Blanchard, Ph.D., who assumed the role of inhibitor where extended and simultaneous exposure of the two chief executive officer in July and currently sits on Microchips 26 AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBEAROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE

Biotech’s board of directors. “It’s truly an exciting phase in the Cristal Therapeutics develops new therapies against cancer and company’s lifecycle as we continue to advance the development other diseases, such as chronic inflammatory disorders, by using of our contraceptive implant and focus our efforts on forming its patented CriPec® technology to entrap existing and new strategic partnerships that leverage our platform to enhance the drugs in polymer nanoparticles of 0.0001 mm diameter. These utility and compliance of new and established therapeutic agents nanoparticles provide better distribution throughout the body to manage osteoporosis, diabetes, and other chronic conditions and a more selective release of the drugs, such as anticancer that require frequent, long-term dosing.” drugs in the case of tumors. Therefore, products based on CriPec® may provide improved efficacy and fewer side effects, Microchips was cofounded by renowned MIT researchers offering improved treatment of various diseases. Robert Langer, Ph.D., and Michael J. Cima, Ph.D., who designed the novel technology and published the first study on In a range of studies performed since 2011, Cristal Therapeutics its viability as a long-term drug delivery platform implant in has demonstrated the safety and efficacy of various CriPec® Nature. Over the last decade, the safety and viability of the nanomedicines in preclinical studies. In the next few years, the microchip-based implant have been extensively studied in animal first product, CriPec® docetaxel for the treatment of cancer, will models and humans and have been documented in peer-reviewed be developed further and tested on humans. If successful, this journals. In 2012, Microchips Biotech conducted a first-in- will enable chemotherapy to proceed more selectively and human study in women with osteoporosis, demonstrating the efficiently, with fewer undesirable side effects. Early in 2015, the ability of its platform to deliver the same therapeutic level of a first clinical study to evaluate CriPec® docetaxel will commence. drug to increase bone mass as achieved via daily injections. In the same year, the company received grants to develop a microchip- Dr. Joost Holthuis, the new CEO of Cristal Therapeutics, based, long-term, reversible contraceptive implant for women in comments on this financing round: “Chemelot Ventures joining developing countries who have limited access to routine medical our group of preeminent investors represents a growing care and modern contraceptive options. commitment to nanomedicine. The continuing commitment and support of our existing investors is extremely important to our “The versatility of our platform design lends itself to several business. That commitment reflects the potential of the drug clinical applications, and diabetes management is one specific candidates developed by Cristal Therapeutics on the basis of the area of tremendous opportunity, a fact that is underscored by our CriPec® technology.” discussions with several potential partners focused on managing that condition,” added Dr. Blanchard, who was formerly senior Marcel Kloosterman, investment manager of Chemelot Ventures: vice president and chief scientific officer of Zimmer, Inc. “For “We are impressed by the focus, knowledge, and commitment of patients with diabetes, compliance is critical and a challenge given the Cristal Therapeutics management team. We are pleased to the need for frequent, even twice-daily administration of support the company in its efforts to develop a unique new therapeutics, often via injections. Leveraging the microchip-based treatment for patients with solid tumors. Cristal Therapeutics’ implant to automate dosing to enhance compliance could be life- technology is enabling a more effective use of existing medicines changing for the 29 million Americans living with the disease.” with fewer side effects for the patient and also demonstrates its social relevance. Additionally, Cristal Therapeutics is contributing Under Dr. Blanchard’s leadership, Microchips updated its visual to a substantial increase in high-grade biopharmaceutical corporate identity with new corporate branding and a revamped knowledge in our Limburg region in the Netherlands. We look corporate website (www.microchipsbiotech.com) that reflects the forward to the start of the first clinical study with great company’s new vision and long-term goals. confidence.”

€6 Million in New Capital and New CEO for Cristal Cofounder Dr. Joost Holthuis has succeeded its founder Dr. Therapeutics Cristianne Rijcken as CEO of the company, effective since Business Wire: December 15, 2014 – MAASTRICHT, The December 1, 2014. Dr. Holthuis has an extensive career in the Netherlands – Biopharmaceutical company Cristal Therapeutics biotech field and founded OctoPlus, which was listed on the has completed a new financing round of over €6 million that Amsterdam stock exchange, and was CEO between 1995 and includes investments from new and existing investors and a 2008. In addition to serving on supervisory boards of various national innovation fund. Venture capital investor Chemelot highly promising biotech startups, Dr. Holthuis is also a venture Ventures joins as a new shareholder, and existing investors Thuja partner at biotech venture capital investor BioGeneration in Capital, BioGeneration Ventures, Nedermaas, Utrecht University Naarden. Holding, and Beheer Innovatiefonds Provincie Limburg also contributed. The financing will be used to launch the first clinical Dr. Rijcken, CEO since its incorporation in 2011, will become study of Cristal Therapeutics’ most advanced therapy, CriPec® chief scientific officer (CSO). Dr. Rijcken, together with Joost docetaxel. Joost Holthuis, cofounder of Cristal Therapeutics and Holthuis, launched Cristal Therapeutics as a spinoff of the former CEO of OctoPlus, has also been appointed CEO with Department of Pharmaceutics of Utrecht University. effect from December 1. In the News continued on page 28 27 AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE

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Joost Holthuis said, “I want to thank Cristianne in particular for one co-pay will be required,” said Nikolaj Sørensen, CEO and her ceaseless commitment to Cristal Therapeutics since our joint president of Orexo AB. start. Her exceptional knowledge and passion for the development of new pharmaceutical therapies will be brought The advanced formulation provided by ZUBSOLV meets the even more to the fore following her appointment as chief needs expressed by patients, such as improved taste and fast scientific officer. I am looking forward to our renewed dissolve time. Meeting patient needs may have the potential to collaboration in this important period of transformation for improve patient adherence, thus reducing relapse rates and Cristal Therapeutics.” improving successful patient outcomes. ZUBSOLV is the only opioid dependence treatment option available in the highest level Cristal Therapeutics, established in Maastricht, focuses on the of child resistant, unit dose, F1 packaging, designed to reduce the development of nanomedicines with improved therapeutic chance of unintended pediatric exposure. efficacy. The pipeline comprises products based on drugs in development and also on the market, in combination with the Acorda Announces Initiation of Phase 3 Trial of CVT-301 in patented CriPec® platform, for the treatment of various diseases, Parkinson’s Disease including cancer and chronic inflammatory disorders. Business Wire: December 10, 2014 – ARDSLEY, NY, U.S.A. – Acorda Therapeutics, Inc. (Nasdaq: ACOR) today ® CriPec transforms drugs into polymer nanoparticles via an announced that the first patient has been enrolled in a phase 3 innovative process. These nanoparticles provide improved study of CVT-301 for the treatment of OFF episodes in distribution throughout the body. The substantial improvement Parkinson’s disease (PD). OFF episodes are characterized by a ® of the efficacy and safety of the drugs entrapped in CriPec re-emergence of PD symptoms such as tremor, muscle stiffness, nanoparticles has already been demonstrated in animal studies. and impaired ability to move. Cristal Therapeutics has demonstrated the benefits of CriPec® for various molecules, including peptide drugs (an anticancer CVT-301 is a novel, self-administered inhaled therapy designed drug transported by a protein that is important for the tumor), as to provide rapid, reliable delivery of a precise dose of levodopa well as for applications such as active targeting for more selective (L-dopa) through the lungs to return people with PD to an ON treatment. The results to date have contributed to the company’s state. An ON state is when a patient’s symptoms are adequately present innovative product portfolio. controlled, allowing people with Parkinson’s to more readily Orexo: FDA Approves Two Higher Dosage Strengths of perform daily activities. ZUBSOLV® “Parkinson’s is a debilitating neurological disease affecting over a Business Wire: December 12, 2014 – UPPSALA, SWEDEN – million Americans and as many as 10 million people worldwide,” Orexo AB (publ) (STO: ORX) announced today that it has said Enrique Carrazana, M.D., Acorda Therapeutics’ chief received approval from the U.S. Food and Drug Administration medical officer. “About 350,000 people with PD in the United (FDA) of two higher dosage strengths of ZUBSOLV States experience OFF episodes, which can be exceptionally (buprenorphine/naloxone CIII sublingual tablet) for disruptive, impacting their lives on a daily basis, even multiple maintenance treatment of opioid dependence. The new dosage times per day. We believe CVT-301 has the potential to be an strengths are 8.6 mg/2.1 mg and 11.4 mg/2.9 mg important treatment for people experiencing OFF episodes.” buprenorphine/naloxone CIII sublingual tablets. The 8.6 mg/2.1 mg dosage strength is expected to be launched early 2015 and The multicenter, double blind, randomized trial is expected to the 11.4 mg/2.9 mg strength later in 2015. enroll approximately 345 participants across three arms: 50 mg, 35 mg, or placebo. These are the same doses used in the phase 2b The new dosage strengths complement the existing strengths of study. The primary outcome measure is improvement on the 5.7 mg/1.4 mg and 1.4 mg/0.36 mg tablets and enable patients Unified Parkinson’s Disease Rating Scale (UPDRS) Part III to receive their optimal dose in one tablet. The new strengths are after administration of CVT-301. made with the advanced, proprietary sublingual tablet formulation in ZUBSOLV, providing higher bioavailability, a More details about the study, including enrollment criteria, can fast dissolve time, small tablet size, and menthol flavor. be found at www.acorda.com or http://clinicaltrials.gov/ct2/ show/NCT02240030?term=CVT-301&rank=2. “Orexo remains fully committed to advancing the treatment of opioid dependence. During the summer, we received positive Positive results from the CVT-301 phase 2b study were presented data from the largest clinical trials ever conducted in this disease at the 2014 American Academy of Neurology Annual Meeting. area. Today, we are proud to announce that the FDA has In this study, participants receiving CVT-301 showed a approved two additional dosage strengths of ZUBSOLV. These statistically significant and clinically important reduction in higher dosage strengths will allow more patients to get the right average UPDRS Part III motor score versus placebo across time dosage in only one tablet and thus reduce the need to combine points beginning at 10 and up to 60 minutes postadministration different dosage strengths. This will improve patient convenience (P < 0.001). Both doses of CVT-301 were well tolerated, with no and adherence while reducing their out-of-pocket cost, as only increase relative to placebo in troublesome or nontroublesome 28 AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBEAROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE

dyskinesias during ON periods. There were no serious adverse neurological therapies. Acorda is currently developing a number events in the trial, and the incidence of drug-related adverse of clinical and preclinical stage therapies. This pipeline addresses events was similar between treatment groups. The CVT-301 a range of disorders including poststroke walking deficits, inhaler was shown to be easily self-administered in the OFF state. Parkinson’s disease, epilepsy, neuropathic pain, heart failure, MS, and spinal cord injury. For more information, please visit the “Oral L-dopa is the standard of care in reducing the symptoms company’s website at www.acorda.com. of PD; however, significant challenges remain in creating an individualized treatment regimen that consistently maintains November therapeutic effects as the disease progresses,” said Rick Batycky, Generex Announces Participation in MedCannAccess®– Ph.D., Acorda Therapeutics’ chief technology officer. “CVT-301 CannScience Partnership on Nonsmoked Forms of uses our proprietary ARCUS technology to deliver L-dopa Marijuana through the lungs. The ARCUS technology can deliver much larger doses than is possible with standard pulmonary PRNewswire: November 17, 2014 – WORCESTER, MA, technologies, making it ideal for delivery of medications such as U.S.A. and TORONTO, Canada – Generex Biotechnology L-dopa.” Corporation (www.generex.com) (OTCBB: GNBT) today announced its participation in a MedCannAccess (www. Acorda’s proprietary ARCUS technology platform is a dry- MedCannAccess.com) partnership with CannScience powder pulmonary delivery system that has potential Innovations Inc. applications in multiple disease areas. This platform allows consistent and precise delivery of significantly larger doses of MedCannAccess today announced that it has acquired a medication than are possible with conventional pulmonary substantial minority equity stake in CannScience, a leading systems. The ARCUS inhaler is breath-actuated, operated by the cannabinoid drug development firm. This partnership positions user putting their lips to the device and simply breathing in. MedCannAccess to be a leader in the development of pharmaceutical cannabinoid products. The ARCUS technology has been used to successfully deliver more than one million doses to patients in clinical trials of “Successful companies in the cannabis industry will have three various products. CVT-301 is the most advanced drug candidate legs to their platform: quality production, an effective patient using the ARCUS technology. Acorda has an extensive patent acquisition and retention strategy, and innovative research and portfolio relating to CVT-301 and the ARCUS technology, development capabilities,” said Rade Kovacevic, vice president of which covers aspects of the formulated drug product, the inhaler, business development at MedCannAccess. “We believe we have the method of drug delivery, and manufacturing processes for strong positions already in the first two legs, and through this CVT-301. investment, we have solidified the R&D piece of our platform, positioning us as a leader in future cannabinoid drug CVT-301 is being developed as a self-administered, inhaled development. Physicians and patients alike have been calling for L-dopa therapy for treatment of OFF episodes in Parkinson’s access to cannabinoid products that do not require smoking or disease (PD). This is an adjunctive therapy to a patient’s inhalation; this partnership will allow us to take that significant individually optimized oral L-dopa regimen. Acorda’s proprietary step forward.” ARCUS® technology provides a precise dose of a dry powder formulation of L-dopa to the lung to enable rapid and CannScience is an R&D biopharmaceutical company established predictable absorption. CVT-301 is delivered through a pocket- in Toronto, Canada, to conduct research and product size, breath-actuated inhaler designed to be patient friendly. In development for extracts and formulations related to medical the CVT-301 treatment group, lightheadedness and cough were cannabis and its derivatives. CannScience is developing the most frequently reported adverse events. There were no proprietary technologies and owns know-how related to the observed, treatment-associated adverse effects on lung function. chemistry and pharmacology of cannabinoids and potentially Clinical studies conducted to date have been funded in part by how they integrate with various medical devices and drug grants from the Michael J. Fox Foundation for Parkinson’s delivery technologies. CannScience intends to develop Research. commercial-ready products and obtain regulatory approval for RapidMist™ in the Canadian and international jurisdictions. Founded in 1995, Acorda Therapeutics is a biotechnology The company’s founders have a wealth of experience in the life company focused on developing therapies that restore function sciences industry and access to laboratories at some of the top and improve the lives of people with neurological disorders. research institutions in Canada.

Acorda markets three FDA-approved therapies, including “CannScience is working to develop its product pipeline, which AMPYRA® (dalfampridine) extended release tablets, 10 mg, a will include proprietary drug, device, and delivery technologies,” treatment to improve walking in patients with multiple sclerosis said Har Grover, the CEO of CannScience. On November 18, (MS), as demonstrated by an increase in walking speed. The company has one of the leading pipelines in the industry of novel In the News continued on page 30 29 AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBEAROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE

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2014, CannScience entered into a nonbinding letter of intent made it possible to keep the essential components of a battery, with Generex to license Generex’s proprietary RapidMist™ drug the solid electrode and liquid electrolyte, separated until power is delivery technologies to CannScience for the buccal delivery of needed. This battery system can be activated electronically, cannabis-derived products into the bloodstream. mechanically, or via gravitational pull.

MedCannAccess was established to provide access to the highest mPhase Technologies Inc. (XDSL) is a 2013 Frost and Sullivan quality of medical cannabis products developed through research recipient for the North American Advanced Battery Technology and innovation, aiming to improve the quality of life for persons Innovation Award. mPhase Technologies is a publicly traded with a wide range of conditions including chronic disabilities company (XDSL) that is pioneering a revolutionary smart sur- and terminal illnesses. MedCannAccess is a proud member of face technology enabled by breakthroughs in nanotechnology, the Canadian Medical Cannabis Industry Association, Toronto MEMS processing, and microfluidics. Our smart surface tech- Board of Trade, Guelph Chamber of Commerce, and Ontario nology has potential applications within drug delivery systems, Chamber of Commerce. lab-on-a-chip analytic systems, self-cleaning systems, liquid and chemical sensor systems, and filtration systems. mPhase has pio- mPhase Technologies’ Smart Drug Delivery System Holds neered its first smart surface enabled product, the mPhase smart Significant Portion of Patentable Claims nanobattery, still in development. More information about the Business Wire: November 17, 2014 – CLIFTON, NJ, U.S.A. – company can be found at www.mPhaseTech.com. mPhase Technologies, Inc. (XDSL) (http://mphasetech.com/), Catalent Acquires Micron Technologies announced an update on the drug delivery system patent application that was originally filed in February 2013. The drug Business Wire: November 13, 2014 – SOMERSET, NJ, delivery system is based on mPhase Technologies’ award-winning U.S.A. – Catalent, Inc. (NYSE: CTLT), the leading global advanced battery technology. Frost and Sullivan recognized provider of advanced delivery technologies and development mPhase with its 2013 North American Advanced Battery solutions for drugs, biologics, and consumer health products, Technology Innovation Award for Best Practices. today announced that it has acquired Micron Technologies, a leading global provider of particle size engineering technologies. In December 2013 the patent application for the smart drug delivery system received a first review (Office Action) by the In an important advance in executing its strategy to provide U.S. Patent and Trademark Office. The patent office examiner the best drug delivery technologies and the broadest drug indicated that a significant portion of the claims were patentable. development expertise, Catalent will add Micron Technologies’ A response to the office was filed, without amending the claims, superior particle size engineering capabilities to its industry- but with strong arguments as to why all of the claims are leading suite of drug delivery and development solutions. patentable. mPhase is now waiting for a response from the patent Catalent can now partner with more pharmaceutical innovators office, which is expected no later than in the first quarter of 2015. at the earliest stages of the drug development process with an unrivaled set of options and expertise. These range from mPhase believes the issuance of a patent could lead to licensing OptiForm® API optimization and Micron Technologies particle opportunities for the novel drug delivery system, possibly size optimization, to expert formulation and final dose form creating greater shareholder value. The drug delivery patent, if design services, through to leading bioavailability solutions such issued, would enable the automatic dispensing of a preset dosage as RP Scherer Softgel lipid systems and OptiMelt™ hot melt of a drug agent or medication. extrusion technologies. Catalent can support its customers all the way through scale-up, clinical, and commercial manufacturing of The field of invention relates to a drug delivery system that finished oral and inhaled dose forms around the world, including generally includes a housing having one or more reservoirs, each for highly potent compounds. having a medical agent hermetically sealed therein. A membrane extends across each of the one or more reservoirs, which is “This strategic acquisition allows Catalent to provide an adapted to allow the medical agents to pass through in response unprecedented set of integrated development solutions and to external stimuli, such as physical puncturing, melting the superior drug delivery technologies to the industry, partnering membranes through use of heating elements, or electrowetting in with our customers’ R&D teams earlier in the development cycle response to a voltage pulse. A wicking material extends across and helping them deliver better treatments to clinic and to the membranes through which the medical agents are dispensed market faster and more efficiently,” said John Chiminski, to a patient. Because the housing can be made flat, the overall Catalent, Inc., president and CEO. “We are pleased to add dispensing device can be reduced in size, allowing the drug Micron Technologies’ leading technologies and manufacturing delivery device to be located and attached to broader areas of the expertise and welcome their highly talented management, patient’s body for expanded medical applications and treatment. scientific, and operations teams to Catalent.”

Under past cooperative research and development agreements Micron Technologies adds to Catalent’s long history of with the U.S. Army, mPhase developed a smart nanobattery that innovation and leadership in the pharmaceutical industry, with

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its proven and versatile portfolio of particle size reduction, receptor found on MPM cells and have been coined TargomiRs micronization, and milling technologies used to overcome for this study. bioavailability, stability, and manufacturability challenges. The MesomiR-1 trial is an open-label, exploratory phase 1 study The acquisition is Catalent’s second since its IPO in July and of TargomiRs administered in escalating doses by intravenous follows the acquisition of Redwood Bioscience, with its infusion in patients with MPM who failed to respond to standard SMARTag™ antibody-drug conjugate (ADC) technology of care therapy. The primary study objectives are to establish the platform, in October 2014. optimal dose of TargomiRs and to detect early signs of disease stabilization. Patients will be carefully followed during an eight- Micron Technologies currently operates two state-of-the-art week period of experimental treatment including measurement of facilities, with excellent quality and regulatory compliance quality of life, pulmonary function, and changes in immune records, in Malvern, Pennsylvania, and in Dartford, United status. Kingdom, and employs approximately 100 people across both sites. Micron Technologies has over 25 years of experience in air Participating sites for the trial include the Northern Cancer jet milling micronization and is capable of processing R&D and Institute, Lifehouse at Royal Prince Alfred Hospital, and commercial volumes at both of its sites. Micron Technologies Concord Repatriation Hospital, all in Sydney. currently supports active programs involving over 300 customers from around the world. Both facilities are equipped with Dr. Himanshu Brahmbhatt, joint CEO of EnGeneIC, said, “We advanced systems to ensure the quality, safety, and total are excited to commence this trial since we believe that it is the containment of highly potent and cytotoxic compounds and to first time a microRNA-based oncology therapeutic will be provide integrated analytical services capabilities from early administered in a thoracic tumor with very limited treatment stage development to commercialization. options and a very poor prognosis. It is also a tremendous opportunity for EnGeneIC to demonstrate the platform nature Joseph Drost, CEO of Micron Technologies, who will continue and versatility of the targeted EDV™ nanocell.” to lead this business, remarked, “We are excited to become part of Catalent, as there is a natural synergy between our Prof. Nico van Zandwijk, who will be the principal investigator organizations, with the global leader in advanced delivery for the MesomiR-1 trial, remarked, “We have previously technologies and development solutions now joining forces with published that miR-16 expression was severely depleted in all a leading provider of particle size engineering technologies and MPM tumor samples tested, which results in tumors growing integrated analytical services. Through access to Catalent’s global unchecked. We are extremely pleased to have teamed up with network, development expertise, and innovative technologies, we EnGeneIC to use its unique targeted nanocell to restore this can jointly provide end-to-end solutions to accelerate drug functional nucleic acid and to demonstrate the safety of the development programs and bring better treatments to patients approach in a group of patients in great need of more effective worldwide.” treatment. “

EnGeneIC and Asbestos Diseases Research Institute EnGeneIC’s bacterially derived EDV™ nanocells are a powerful Initiate MesomiR-1 Phase 1 Trial in Patients with Late nanoparticle drug delivery system designed to directly target and Stage Mesothelioma effectively kill tumor cells with minimal toxicity, while at the PRNewswire: November 10, 2014 – SYDNEY, Australia – same time stimulate the immune system’s natural antitumor EnGeneIC, Ltd., an emerging biopharmaceutical company response. focused on developing its proprietary EDV™ nanocell platform for the targeted delivery of cancer therapeutics and other Intravenously injected EDV™ nanocells exit the leaky vascular therapeutic molecules, announced today that, together with the system only within tumors and attach to cancer cells via a Asbestos Disease Research Institute (ADRI), it has initiated the specially designed, targeted bispecific antibody. Once attached, first clinical trial evaluating its bacterially derived and antibody- the nanocell is able to enter the tumor cell and deliver a drug guided EDV™ nanocells packaged with microRNA for the payload of up to one million drug molecules per nanocell. In treatment of patients with malignant pleural mesothelioma parallel, the bacterial cell wall of the nanocells stimulates key (MPM). The study is the first time a targeted nanotherapeutic components of the immune system, which are then activated to approach to microRNA replacement is being tested in patients seek out and destroy cancer cells. with MPM. EnGeneIC is an emerging biopharmaceutical company focused EnGeneIC’s EDV™ nanocells will be packaged with miR-16 on developing its proprietary EDV™ nanocell platform for the microRNAs, which were discovered to be missing in MPM cells targeted delivery of cancer therapeutic and other therapeutic by Profs. Glen Reid and Nico van Zandwijk of the ADRI. To molecules. The company’s lead technology platform, EDV™ deliver the missing microRNAs to the cells, the EDV™ nanocells utilizes antibody-targeted, bacterially derived, nonliving are designed to specifically target the epidermal growth factor “nanocells” to release high concentrations of chemotherapeutic In the News continued on page 32 31 AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE

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agents, molecularly targeted drugs, and RNA-interference of 0.09 mm). The second trial of 184 patients, which compared molecules directly into targeted tumor cells. In doing so, EDV™ MiStent SES and Medtronic Endeavor® DES, showed lower nanocells enable current cancer treatments to be more potent MACE at three years in the MiStent SES arm (8.3 vs. 15.3%, and far less toxic, while also offering a potential new means for P = 0.2), with a very low rate of reintervention for MiStent SES treating drug-resistant cancers. EnGeneIC is currently preparing (TLR of 2.5% at three years) and no definite or probable stent an IND for FDA submission, with plans to launch a phase 1/2a thrombosis. clinical trial in recurrent glioblastoma patients in early 2015. Trials are also in planning stages for non-small cell lung cancer. MiStent SES has received CE Marking and has not yet been For more information, please visit www.engeneic.com. marketed. STENTYS plans to launch the product in H1 2015 in Europe, to be followed by the many geographies where STENTYS Expands Product Offering to All Coronary Stent STENTYS has built a commercial network. STENTYS and Indications Through Exclusive Agreement with Micell to Micell will partner to conduct MiStent’s postmarket study, Distribute Its Novel Drug-Eluting Stent DESSOLVE III. Business Wire: November 3, 2014 – PRINCETON, NJ, U.S.A., October and PARIS, France – STENTYS (Paris: STNT) (FR0010949404—STNT), a medical technology company CeloNova’s Super-Selective Embolic Microsphere with commercializing the world’s first and only Self-Apposing® Drug Loading Capabilities Could Mean Improved Quality coronary stent, today announced it has entered into a five year of Life and Overall Survival for Liver Cancer Patients agreement with Micell Technologies Inc. to be the exclusive distributor of the MiStent coronary stent worldwide (excluding Business Wire: October 30, 2014 – SAN ANTONIO, TX, the United States, Canada, China, South Korea, and Japan). U.S.A. – CeloNova BioSciences, Inc. (CeloNova), today announced that the U.S. Food and Drug Administration (FDA) Gonzague Issenmann, chief executive officer and cofounder of has granted approval to start an investigational device exemption STENTYS, explains: “We are thrilled to launch this exciting new (IDE) clinical trial for its novel ONCOZENE™ embolic product that is designed to outperform the market-leading work- microspheres, loaded with doxorubicin, a chemotherapy drug horse stents thanks to a unique coating technology. Our custom- used in the treatment of hepatocellular carcinoma (HCC). HCC ers will now have the opportunity to use MiStent for routine pro- is the most common primary liver cancer and accounts for cedures and STENTYS Self-Apposing stent for complex vessel approximately 600,000 deaths annually on a worldwide basis. anatomy that requires optimal apposition, both of which are de- Untreated HCC patients have a median survival time of less signed for safe vessel healing and improved patient outcomes.” than 12 months.

“This long-term partnership is one more building block of the CeloNova’s ONCOZENE™ microspheres’ small sizes and company’s growth strategy. With two CE marked sirolimus-elut- precise calibration allow for super-selective embolization ing stents covering all coronary indications and commercialized combined with distal penetration, which may greatly increase the through our fast increasing sales network, we will strengthen our chemotherapeutic impact at the tumor site while lowering the market position, increase access to our target audience, as well as toxicity in other parts of the body, thereby potentially improving create an opportunity for even greater revenue growth,” concluded the patient’s tolerance of the treatment. CeloNova’s Gonzague Issenmann. TANDEM™ microspheres are available in Europe and bear the European Union’s CE mark since it was granted in 2012 for The MiStent sirolimus-eluting absorbable polymer coronary stent embolization of HCC, with or without delivery of doxorubicin. system (MiStent SES®) is a balloon-expandable stent designed for rapid healing and slow progression of coronary artery disease. “Our ONCOZENE™ microspheres platform, when combined The bioabsorbable coating of MiStent SES disappears within with its precise drug delivery capability, presents a potentially three months of implantation to promote fast vessel healing. improved treatment option for liver cancer patients,” said Jane However, sirolimus elution is precisely and consistently controlled Ren, Ph.D., CeloNova’s chief technology officer. “We are very up to nine months after implantation, thereby inhibiting vessel pleased to be working with the leading HCC experts in the renarrowing. These unique properties of both fast polymer world to alleviate the pain of our patients.” absorption and sustained drug release are made possible by an innovative proprietary coating technology that allows sirolimus to “We are excited to move ONCOZENE™ microspheres into a be encapsulated as tiny crystals; once the polymer is gone, the pivotal phase 3 trial,” said Dr. Ghassan Abou-Alfa at Memorial crystals slowly dissolve into the tissue surrounding the stent, Sloan-Kettering Cancer Center. “Early studies have shown that providing a continued local antiproliferative and anti- liver-directed therapies utilizing drug-eluting microspheres such inflammatory effect for several months. as ONCOZENE™ microspheres provide an excellent treatment option for locally advanced HCC patients.” MiStent SES has been studied clinically in the DESSOLVE I and II trials. The first trial on 30 patients showed no reduction in “This IDE trial is designed to develop an evidence-based treat- artery lumen diameter between 8 and 18 months (late lumen loss ment plan for late-stage HCC patients and will enroll patients in 32 AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBEAROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE•AROUNDTHEGLOBE

multiple cancer centers across the United States, Europe, and It is estimated that approximately 2.5 million people in the Asia,” said Dr. Riccardo Lencioni, professor at the Pisa University United States are dependent on prescription opioids or heroin. School of Medicine in Italy and chairman of the World Confer- Despite the availability of effective treatments, including ence on Interventional Oncology (WCIO). Bunavail (buprenorphine and naloxone) buccal film, challenges remain regarding patient adherence to long-term buprenorphine CeloNova CEO Martin Landon commented, “The recent ex- treatment, which is critical to successfully manage opioid panded indication for our ONCOZENE™ and EMBOZENE™ dependence. microspheres, to include embolization of hepatoma, combined with this IDE trial approval for ONCOZENE™ microspheres “Given our significant experience with buprenorphine in both loaded with doxorubicin, represent two more ‘industry first’ ex- opioid dependence and chronic pain, we believe this is an ideal amples of how we are executing on our vision to bring unique and opportunity for BDSI to extend our franchise in both of these disruptive solutions to physicians, patients, and payers that im- areas, as the need remains high,” said Dr. Andrew Finn, executive prove patient care and add significant clinical and economic value vice president of product development for BDSI. “We look to the healthcare community.” forward to working closely with Evonik to expeditiously complete formulation development work and move the product The company announced on September 3, 2014, that the FDA into the clinic late next year. Since this will be a 505(b)(2) had issued 510(k) clearance expanding the indication of its development program, we believe there may be an opportunity to ONCOZENE™ and EMBOZENE™ microspheres products to move toward an NDA submission for opioid dependence in include the treatment of hepatoma, also known as HCC. That approximately three years time.” approval provides support for another treatment option for physicians and patients in their battle against primary liver “Evonik is pleased to work with BDSI on the development of cancer. this novel long-acting buprenorphine product,” said Dr. Jean- Luc Herbeaux, head of Evonik’s global health care business line. CeloNova BioSciences, Inc., headquartered in San Antonio, “With its broad range of competencies in API and drug delivery Texas, is a global medical device company that develops, systems, Evonik strives to support customers in the development manufactures, and markets a family of interventional cardiology and launch of novel medical treatments. Using our proprietary and endovascular products. Our products are developed and FormEZE® microparticle technology and Resomer® manufactured in Carlsbad, California, U.S.A., and Ulm, biomaterials, this pharmaceutical will be manufactured at our Germany. The company’s regional offices are located in Germany, state-of-the-art facility in Birmingham, Alabama.” France, the United Kingdom, the Netherlands, and Austria. For additional information about CeloNova BioSciences, see the “The potential availability of a long-acting formulation of company website at www.celonova.com. buprenorphine has the opportunity to significantly advance the treatment of opioid dependence and furthers our commitment to BioDelivery Sciences to Develop a Long-Acting Injectable this underserved treatment area,” said Dr. Mark A. Sirgo, Depot Formulation of Buprenorphine with Evonik for Use president and chief executive officer. “Not only would a single in Opioid Dependence and Pain monthly injection provide an opportunity to substantially PRNewswire: October 28, 2014 – RALEIGH, NC, U.S.A. – improve adherence to buprenorphine treatment, which is a BioDelivery Sciences International, Inc. (BDSI) (NASDAQ: formidable problem for many patients, it could also help to BDSI), has entered into an exclusive agreement with Evonik eliminate the problem of diversion. We also believe this will be Corporation to develop and commercialize a proprietary, an outstanding companion product to Bunavail and, if approved, injectable microparticle formulation of buprenorphine provides another product for our existing sales team.” potentially capable of providing 30 days of continuous therapy following a single subcutaneous injection. As part of the agreement, BDSI will have the right to license the product(s) following the attainment of phase I ready While BDSI plans to pursue an indication for the maintenance formulations. At that point, Evonik could receive downstream treatment of opioid dependence, the company has also secured payments for milestones related to regulatory filings and the rights and plans to develop a product for the treatment of subsequent NDA approvals as well as product royalties. Evonik has the exclusive rights to develop the formulation and chronic pain in patients requiring continuous opioid therapy. n BDSI has also secured options to license Evonik-owned manufacture the product(s). intellectual property related to these products.

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